1
|
Zhao H, Liu Y, Zhu L, Cheng J, Li Y. MAD2L1-mediated NANOG nuclear translocation: A critical factor in lung cancer chemoresistance. Cell Signal 2025; 132:111811. [PMID: 40233918 DOI: 10.1016/j.cellsig.2025.111811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/21/2025] [Accepted: 04/11/2025] [Indexed: 04/17/2025]
Abstract
This study investigates the function of Mitotic Arrest Deficient 2 Like 1 (MAD2L1) and its role in facilitating NANOG nuclear localization, contributing to chemoresistance in lung cancer. Using both in vivo and in vitro models, we examined MAD2L1 expression in Carboplatin-resistant lung cancer cell lines. The study utilized gene knockdown and overexpression techniques to assess MAD2L1's role in chemoresistance and cell stemness, alongside co-expression analysis and fluorescence staining and CO-IP to explore MAD2L1 and NANOG interactions. Results showed a marked increase in MAD2L1 expression in resistant lung cancer cells, correlating with enhanced cell stemness. MAD2L1 knockdown heightened sensitivity to Carboplatin and reduced NANOG expression, while MAD2L1 overexpression led to increased resistance and stemness. Mechanistically, MAD2L1 facilitated NANOG's nuclear localization, with their co-expression linked to increased cell resistance and metastasis in vivo. These findings suggest that MAD2L1 enhances chemoresistance by promoting NANOG localization, offering insights into potential therapeutic targets for overcoming lung cancer chemoresistance.
Collapse
Affiliation(s)
- Hongye Zhao
- The Department of Dermatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Yongcun Liu
- The Department of Surgery, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang 050011, China
| | - Longyu Zhu
- The Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Jingge Cheng
- The Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
| | - Yishuai Li
- The Department of Thoracic Surgery, Hebei Provincial Key Laboratory of Pulmonary Disease, Hebei Chest Hospital, Shijiazhuang 050047, China.
| |
Collapse
|
2
|
Luo Y, Li D, Yang Q, Dong Y, Chen W. Treatment of RET/ALK comutated advanced lung large cell neuroendocrine carcinoma: a case report and literature review. Anticancer Drugs 2025; 36:509-512. [PMID: 40112204 DOI: 10.1097/cad.0000000000001715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
The prognosis of advanced lung large-cell neuroendocrine carcinoma is poor, and the efficacy of targeted therapy is still being explored. A case of RET fusion mutation combined with ALK rearrangement positive advanced lung complex large cell neuroendocrine carcinoma was reported. The patient developed intrapulmonary and bone metastases 8 months after chemotherapy after lung cancer surgery, RET fusion mutations were detected by genetic testing, and intracranial progression occurred 1 year after pilatinib was applied. The comutation of RET and ALK was detected by genetic testing, and the pulmonary progression occurred 2 months after the application of aletinib, after being treated with pilatinib and aletinib, he progressed again in 9 months. We point out that large cell neuroendocrine carcinoma complex patients with RET gene mutation can benefit from targeted therapy, and when drug resistance is accompanied by ALK comutation, the patient can benefit from the treatment of the aletinib combined with pilatinib targeted therapy and the side effect is slight. At the same time, we further explore the resistance mechanism of targeted therapy in lung cancer.
Collapse
Affiliation(s)
- Ying Luo
- Department of Radiation Oncology, Taizhou Central Hospital, Jiao jiang Street, Taizhou, Zhejiang, China
| | | | | | | | | |
Collapse
|
3
|
Román-González A, Califano I, Concepción-Zavaleta M, Pitoia F, Salgado SA. Systemic therapies for medullary thyroid carcinoma: state of the art. Ther Adv Endocrinol Metab 2025; 16:20420188251336091. [PMID: 40356795 PMCID: PMC12066861 DOI: 10.1177/20420188251336091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 04/01/2025] [Indexed: 05/15/2025] Open
Abstract
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor accounting for less than 5% of all thyroid cancers. An estimated 25% of cases are familial secondary to a germline mutation on the rearranged during transfection proto-oncogene (RET); this gene can be present as a somatic mutation in approximately 40%-60% of sporadic MTC tumors. There is an existing genotype-phenotype correlation in the clinical behavior of MTC, with the RET M918T variant associated with aggressive disease. The current systemic treatment profile for progressive metastatic MTC involves antiangiogenics multikinase inhibitors (MKI), specifically cabozantinib and vandetanib, and high-specific RET inhibitor therapy. Decisions on the timing of systemic therapy initiation in this population should involve multidisciplinary care and individualization on a case-by-case scenario; a comprehensive evaluation of performance status, tumor burden, progression rate, medical comorbidities, possible medication interactions, and goals of care must be considered in a patient-centered approach. This review summarizes the evidence on the safety, efficacy, and limitations of systemic therapies for MTC; the aim is to empower clinicians with the knowledge to optimally manage patients with advanced, progressive, or metastatic MTC.
Collapse
Affiliation(s)
- Alejandro Román-González
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Universidad de Antioquia, (University of Antioquia), Cra. 51d No. 62-29, Medellín 050001, Colombia
| | - Ines Califano
- Endocrinology Service, Instituto de Oncología “Angel H. Roffo” (Angel H. Roffo Institute of Oncology), University of Buenos Aires, Buenos Aires, Argentina
| | - Marcio Concepción-Zavaleta
- Carrrera de Medicina Humana Universidad Científica del Sur (Scientific University of the South), Lima, Peru
| | - Fabian Pitoia
- Division of Endocrinology, Hospital de Clínicas (Clinics Hospital), University of Buenos Aires, Buenos Aires, Argentina
| | | |
Collapse
|
4
|
Pisapia P, Iaccarino A, Troncone G, Malapelle U. Liquid Biopsy in Solid Tumours: An Overview. Cytopathology 2025. [PMID: 40219616 DOI: 10.1111/cyt.13485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/14/2025]
Abstract
The advent of personalised and precision medicine has radically modified the management and the clinical outcome of cancer patients. However, the expanding number of predictive, prognostic, and diagnostic biomarkers has raised the need for simple, noninvasive, quicker, but equally efficient tests for molecular profiling. In this complex scenario, the adoption of liquid biopsy, particularly circulating tumour DNA (ctDNA), has been a real godsend for many cancer patients who would otherwise have been denied the benefits of targeted treatments. Undeniably, ctDNA analysis has several advantages over conventional tissue-based analysis. One advantage is that it can guide treatment decision making, especially when tissue samples are scarce or totally unavailable. Indeed, a simple blood test can inform clinicians on patients' response or resistance to targeted therapies, help them monitor minimal residual disease (MRD) after surgical resections, and facilitate them with early cancer detection and interception. Finally, an equally important advantage is that ctDNA analysis can help decipher temporal and spatial tumour heterogeneity, a mechanism highly responsible for therapeutic resistance. In this review, we gathered and analysed current evidence on the clinical usefulness of ctDNA analysis in solid tumours.
Collapse
Affiliation(s)
- Pasquale Pisapia
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Antonino Iaccarino
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| |
Collapse
|
5
|
Chung C, Umoru G. Prognostic and predictive biomarkers with therapeutic targets in nonsmall-cell lung cancer: A 2023 update on current development, evidence, and recommendation. J Oncol Pharm Pract 2025; 31:438-461. [PMID: 38576390 DOI: 10.1177/10781552241242684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2024]
Abstract
BackgroundSince the publication of the original work in 2014, significant progress has been made in the characterization of genomic alterations that drive oncogenic addiction of nonsmall cell lung cancer (NSCLC) and how the immune system can leverage non-oncogenic pathways to modulate therapeutic outcomes. This update evaluates and validates the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in NSCLC.Data sourcesWe performed a literature search from January 2015 to October 2023 using the keywords non-small cell lung cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, circulating tumor DNA, predictive and prognostic biomarkers, and targeted therapies.Study selection and data extractionWe identified, reviewed, and evaluated relevant clinical trials, meta-analyses, seminal articles, and published clinical practice guidelines in the English language.Data synthesisRegulatory-approved targeted therapies include those somatic gene alterations of EGFR ("classic" mutations, exon 20 insertion, and rare EGFR mutations), ALK, ROS1, BRAF V600, RET, MET, NTRK, HER2, and KRAS G12C. Data for immunotherapy and circulating tumor DNA in next-generation sequencing are considered emerging, whereas the predictive role for PIK3CA gene mutation is insufficient.ConclusionsAdvances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.
Collapse
Affiliation(s)
- Clement Chung
- Department of Pharmacy, Houston Methodist West Hospital, Houston, TX, USA
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| |
Collapse
|
6
|
Hoe HJ, Solomon BJ. Treatment of non-small cell lung cancer with RET rearrangements. Cancer 2025; 131 Suppl 1:e35779. [PMID: 40171987 PMCID: PMC11963222 DOI: 10.1002/cncr.35779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/28/2024] [Accepted: 09/13/2024] [Indexed: 04/04/2025]
Abstract
Aberrant activation of the RET oncogene by mutations or gene fusions drives various malignancies, including 1%-2% of all non-small cell lung cancers (NSCLCs) that harbor RET gene fusions. Initial attempts to target RET fusion-positive NSCLC with poorly selective multikinase RET inhibitors were associated with significant toxicities and limited efficacy. Two highly potent and selective RET small-molecule inhibitors, selpercatinib and pralsetinib, were granted accelerated approval for advanced RET fusion-positive NSCLC by the US Food and Drug Administration, and have been shown to be highly effective both in treatment-naive and previously treated patients with NSCLC. Selpercatinib has shown superiority over chemotherapy in a phase 3 study (LIBRETTO-431) in previously untreated patients with RET fusion-positive NSCLC, which established its place as the standard of care in this patient population. This review discusses the biology and clinical characteristics of RET-rearranged NSCLC and summarizes the evolution of treatment strategies, current understanding of mechanisms of resistance, and development of new-generation agents to overcome resistance.
Collapse
Affiliation(s)
- Hui Jing Hoe
- Department of Medical OncologyPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
| | - Benjamin J. Solomon
- Department of Medical OncologyPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
| |
Collapse
|
7
|
Xu M, Wu K, He R, He J, Yang G, Ma H, Peng L, Zhang S, Tan L, Zhang Z, Cai Q. Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R). Eur J Med Chem 2025; 286:117294. [PMID: 39879936 DOI: 10.1016/j.ejmech.2025.117294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 01/31/2025]
Abstract
RET is a well-recognized drug target for cancer treatment. Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. RET G810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against Selpercatinib and Pralsetinib. Therefore, there is an urgent need for the development of next-generation RET inhibitors to overcome acquired solvent-front resistance mutations. In this study, a series of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives have been identified as selective next-generation RET inhibitors. The representative compound, CQ1373 exhibits potent cellular potency with IC50 values of 13.0, 25.7 and 28.4 nM against BaF3 cells expressing CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R, respectively. A comprehensive selectivity profile across 89 kinases reveals that CQ1373 demonstrates good selectivity toward wild-type RET and solvent front mutants G810C/R with IC50 values of 4.2, 7.1 and 32.4 nM, respectively. Furthermore, western blot analysis reveals that CQ1373 effectively inhibits RET phosphorylation and downstream signaling through SHC. It also induces apoptosis and cell cycle arrest in a dose-dependent manner in BaF3 cells harboring CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R fusions. More significantly, CQ1373 exhibits promising in vivo anti-tumor efficacy in a CCDC6-RET-G810R mice xenograft model, highlighting its potentials for RET-driven cancers treatment.
Collapse
Affiliation(s)
- Mingjin Xu
- College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Kaifu Wu
- College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Rui He
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Jiahuan He
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Gangpeng Yang
- College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China
| | - Haowen Ma
- College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China
| | - Lijie Peng
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Shuyao Zhang
- Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510632, China
| | - Li Tan
- College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China.
| | - Zhang Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China; Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510632, China.
| | - Qian Cai
- College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China.
| |
Collapse
|
8
|
Mullally WJ, O'Leary CG, O'Byrne KJ. Rearranged during transfection (RET) lung cancer - Update on targeted therapies. Lung Cancer 2025; 200:108083. [PMID: 39827484 DOI: 10.1016/j.lungcan.2025.108083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/18/2024] [Accepted: 01/07/2025] [Indexed: 01/22/2025]
Abstract
The enhanced comprehension of the molecular pathways underpinning oncogenesis in non-small cell lung cancer (NSCLC) has led to the advancement of personalized treatment for individuals with actionable mutations using targeted therapies. The rearranged during transfection (RET) proto-oncogene, is critical in the embryonic development of various tissues, including renal, neural, and neuroendocrine tissue. RET fusions have been observed in approximately 1-2% of NSCLC cases. Targeted therapies for NSCLC with RET alterations have progressed significantly over the past decade. While multikinase inhibitors (MKIs) faced limitations in efficacy and tolerability, the introduction of selective RET inhibitors (SRIs) such as selpercatininb and pralsetinib has transformed patient outcomes, resulting in deep and durable responses. Ongoing clinical trials are exploring their potential benefits in the neoadjuvant and adjuvant setting. Early phase clinical trials endeavor to demonstrate next-generation selective RET inhibitors can effectively overcome SRI resistance mechanisms, offer improved safety profiles, and enhance patient outcomes.
Collapse
Affiliation(s)
- W J Mullally
- Department of Medical Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
| | - C G O'Leary
- Department of Medical Oncology, Mater Misericordiae Hospital, South Brisbane, Queensland 4101, Australia
| | - K J O'Byrne
- Department of Medical Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia; The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia; Translational Research Institute, Woolloongabba, Queensland 4102, Australia.
| |
Collapse
|
9
|
Wang S, Wang Y, Wu X, Yang L, Zhang X. Patients outcomes in lung adenocarcinoma transforming to small-cell lung cancer after tyrosine kinase inhibitor therapy. World J Surg Oncol 2025; 23:34. [PMID: 39893475 PMCID: PMC11787757 DOI: 10.1186/s12957-025-03687-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 01/24/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) transforming to small cell lung cancer (SCLC) is one of the mechanisms of resistance to tyrosine kinase inhibitors (TKIs). Cases of NSCLC transforming into SCLC have been discovered. However, we lack concentrated data on the characteristics of this population and the transformed SCLC to aid our insight of the biology and clinical value of NSCLC transforming with positive. METHODS We systematically reviewed the published literatures and summarized the pathological and clinical characteristics, and the prognosis, of published cases. RESULTS 140 patients with lung adenocarcinoma (LUAD) were included in this study, with a median age of 56.8 years. The median time from the first diagnosis of LUAD transforming to SCLC (ttSCLC) was 20.0 months. The median overall survival (mOS) after the diagnosis of SCLC was 11.0 months (95% CI, 7.41 to 14.59 months). In the univariate analysis, ever smoking (either former or current) was a promising predictor of a shorter ttSCLC (HR, 1.73; 95% CI, 1.14 to 2.62; P = 0.010). TKIs therapy administered as a second line and beyond treatment was related to a significant delay in SCLC onset compared to first-line therapy (HR, 0.62; 95% CI, 0.40 to 0.96; P = 0.031). The median progression-free survival (mPFS) on first-line platinum plus etoposide after the conversion to SCLC was 3.0 months. Female appeared to be related to worse outcomes after transformation of SCLC. CONCLUSION Transformed SCLC exhibited poor response to primary SCLC classic chemotherapy and immunotherapy. It carries a worse prognosis. Exploring novel therapeutic strategies for transformed SCLC is imperative.
Collapse
Affiliation(s)
- Shuai Wang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China
| | - Yongsen Wang
- Department of Molecular Pathology, Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xuan Wu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China
| | - Li Yang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China
| | - Xiaoju Zhang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China.
| |
Collapse
|
10
|
Clifton-Bligh RJ. Mechanisms of resistance to RET-directed therapies. Endocr Relat Cancer 2025; 32:e240224. [PMID: 39655713 PMCID: PMC11798414 DOI: 10.1530/erc-24-0224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/27/2024] [Accepted: 12/10/2024] [Indexed: 01/12/2025]
Abstract
The association between RET and multiple endocrine neoplasia type 2 was established in 1993 and remains one of the very few oncogenes for which distinct phenotypes (medullary thyroid cancer or pheochromocytoma) are associated with the same hot-spot variants occurring in either germline or somatic DNA. Somatic RET fusion events have also been described in several cancers, including papillary thyroid cancer, non-small-cell lung cancer, breast cancer, salivary gland cancer and pancreatic cancer. Highly selective RET inhibitors have improved outcomes in RET-altered cancers and have been well-tolerated. Nevertheless, primary and acquired drug resistance has been observed, arising from distinct genomic alterations either in RET (on-target resistance) or via alternate oncogenic pathways (bypass resistance). The same mechanisms of resistance have been observed across multiple cancer types, which implies RET-altered cancers evolve away from RET addiction via stochastic subclonal events. Understanding these mechanisms is crucial for identifying therapeutic opportunities to overcome resistance. Successful treatment targeting bypass oncogenes has been reported in several instances, at least for short-term outcomes; in contrast, although several compounds have been reported to overcome on-target RET alterations, none have yet been translated into routine clinical practice and this remains an area of urgent clinical need.
Collapse
Affiliation(s)
- Roderick J Clifton-Bligh
- Cancer Genetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia
| |
Collapse
|
11
|
Mina SA, Shanshal M, Leventakos K, Parikh K. Emerging Targeted Therapies in Non-Small-Cell Lung Cancer (NSCLC). Cancers (Basel) 2025; 17:353. [PMID: 39941723 PMCID: PMC11816067 DOI: 10.3390/cancers17030353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/13/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer. Newer advances in common and novel oncogenic drivers continue to occur at vigorous speed, making it challenging to stay up to date with the rapidly evolving field. In this article, we review the emerging perspectives in the treatment of actionable targets in lung cancer. We focus on the development of newer KRAS-directed therapies, particularly on non-G12C mutations, pan-RAS inhibitors, and RAS-GTP inhibitors. We also describe the current standard of care for EGFR- and ALK-altered NSCLC and dive into the novel treatments expected to be in the clinic soon. A similar approach is taken toward MET, HER2, RET, ROS1, and FGFR alterations as emerging targets in non-small-cell lung cancer. Finally, we conclude this review with the current body of evidence for targeting TROP-2 as a novel target, potentially of importance in post-targeted therapy scenarios.
Collapse
Affiliation(s)
- Syeda A. Mina
- Division of Hematology and Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | | | | | - Kaushal Parikh
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| |
Collapse
|
12
|
Lucibello F, Gounant V, Aldea M, Duruisseaux M, Perol M, Chouaid C, Bennouna J, Fallet V, Renault A, Guisier F, Giroux-Leprieur E, Wislez M, Toffart AC, Mazieres J, Basse C, Hegarat N, Carton M, Girard N. Real-World Outcomes of Pralsetinib in RET Fusion-Positive NSCLC. JTO Clin Res Rep 2025; 6:100743. [PMID: 39850629 PMCID: PMC11754132 DOI: 10.1016/j.jtocrr.2024.100743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/02/2024] [Accepted: 09/22/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Pralsetinib is a RET inhibitor found to have antitumor activity in advanced, metastatic, RET fusion-positive NSCLC. Objective To assess real-world efficacy of pralsetinib and treatment sequences in patients with RET fusion-positive NSCLC. Design Retrospective study of consecutive patients enrolled in the French expanded-access program for pralsetinib from December 1, 2019, to December 31, 2021. Participants A total of 41 patients with advanced, refractory, RET fusion-positive NSCLC were included. Pralsetinib was administered at a daily dose of 400 mg based on safety and pharmacokinetic outcomes from previous phase 1/2 study. Results Pralsetinib was administered as second line in 23 patients (56%) and as third line and beyond in 15 patients (37%). After a median follow-up of 26.3 months, pralsetinib was ongoing in 13 patients. Median real-world progression-free survival was 11.8 (95% confidence interval [CI]: 9.3-15.5) months. Objective response rate was 68% (95% CI: 50%-82%), and disease control rate was 89% (95% CI: 75%-97%). Subsequent line of systemic therapy was initiated in 11 patients. Median overall survival from pralsetinib initiation was 23.8 (95% CI: 16.5-not reached) months. Conclusion In this extensive real-world cohort of patients with advanced or metastatic NSCLC harboring RET fusions, we highlight the antitumor efficacy of pralsetinib, particularly when administered in later treatment lines. We also observe the aggressive nature of disease progression, frequent utilization of chemotherapy and antiangiogenic agents as initial subsequent therapies, and limited insight into resistance mechanisms due to infrequent rebiopsy and genomic profiling at progression.
Collapse
Affiliation(s)
| | - Valérie Gounant
- Université Paris Cité, Service d’Oncologie thoracique & CIC1425 INSERM, Hôpital Bichat Claude Bernard, AP-HP. Nord, Paris, France
| | - Mihaela Aldea
- Gustave Roussy, Oncologie médicale, Villejuif, France
| | | | | | | | | | - Vincent Fallet
- APHP, Service de Pneumologie, Hôpital Tenon, Paris, France
| | | | - Florian Guisier
- Normandie Univ, UNIROUEN, LITIS Lab QuantIF team EA4108, CHU Rouen, and Inserm CIC-CRB 1404, Rouen, France
| | | | - Marie Wislez
- APHP, Service de Pneumologie, Hôpital Cochin, Paris, France
| | | | | | - Clémence Basse
- Institut Curie, Institut du Thorax, Paris, France
- Paris Saclay, UVSQ, UFR Simone Veil, Versailles, France
| | | | | | - Nicolas Girard
- Institut Curie, Institut du Thorax, Paris, France
- Paris Saclay, UVSQ, UFR Simone Veil, Versailles, France
| |
Collapse
|
13
|
Qiao JX, Williams D, Gill P, Li L, Norris D, Tokarski JS, Wong J, Qi H, Hafeji Y, Downes DP, Degnen B, Wang YK, Locke G, Fang H, Yu F, Xu S, Naglich J, Zhang J, Nanjappa P, Dai C, Chourb L, Napoline J, Tester R, Jorge C, Li YX, Mathur A, Barbieri C, Soars MG, Venkatanarayan A, Lees E, Borzilleri RM, Gavai AV, Wichroski M, Dhar TGM. Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase. J Med Chem 2024; 67:19736-19754. [PMID: 39437163 DOI: 10.1021/acs.jmedchem.4c02083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound 39. LDD 39 demonstrated high in vitro inhibitory and degradation potency against both RET wild-type and the two representative mutants, V804M and G810R. Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.
Collapse
Affiliation(s)
- Jennifer X Qiao
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - David Williams
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Patrice Gill
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Ling Li
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Derek Norris
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - John S Tokarski
- Molecular Structure & Design, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Jessica Wong
- Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Huilin Qi
- Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Yamnah Hafeji
- Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Daniel P Downes
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Bill Degnen
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Ying-Kai Wang
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Gregory Locke
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Hua Fang
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Fei Yu
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Songmei Xu
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Joseph Naglich
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Jun Zhang
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Purushothama Nanjappa
- Discovery Pharmacology and in vivo Biology, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Chao Dai
- Discovery Pharmacology and in vivo Biology, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Lisa Chourb
- Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Jonathan Napoline
- Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Richland Tester
- Department of Discovery Synthesis, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Christine Jorge
- Department of Discovery Synthesis, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Yi-Xin Li
- Department of Discovery Synthesis, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Arvind Mathur
- Department of Discovery Synthesis, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Christopher Barbieri
- Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Matthew G Soars
- Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Avinashnarayan Venkatanarayan
- Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Emma Lees
- Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - Robert M Borzilleri
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Ashvinikumar V Gavai
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| | - Michael Wichroski
- Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States
| | - T G Murali Dhar
- Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States
| |
Collapse
|
14
|
Jiang Z, Gu Z, Yu X, Cheng T, Liu B. Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer. Front Oncol 2024; 14:1447678. [PMID: 39582541 PMCID: PMC11581962 DOI: 10.3389/fonc.2024.1447678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/25/2024] [Indexed: 11/26/2024] Open
Abstract
The clinical application of small molecule tyrosine kinase inhibitors (TKIs) has significantly improved the quality of life and prognosis of patients with non-small cell lung cancer (NSCLC) carrying driver genes. However, resistance to TKI treatment is inevitable. Bypass signal activation is one of the important reasons for TKI resistance. Although TKI drugs inhibit downstream signaling pathways of driver genes, key signaling pathways within tumor cells can still be persistently activated through bypass routes such as MET gene amplification, EGFR gene amplification, and AXL activation. This continuous activation maintains tumor cell growth and proliferation, leading to TKI resistance. The fundamental strategy to treat TKI resistance mediated by bypass activation involves simultaneously inhibiting the activated bypass signals and the original driver gene signaling pathways. Some clinical trials based on this combined treatment approach have yielded promising preliminary results, offering more treatment options for NSCLC patients with TKI resistance. Additionally, early identification of resistance mechanisms through liquid biopsy, personalized targeted therapy against these mechanisms, and preemptive targeting of drug-tolerant persistent cells may provide NSCLC patients with more sustained and effective treatment.
Collapse
Affiliation(s)
- Ziyang Jiang
- Department of Emergency Medicine and Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhihan Gu
- Department of Emergency Medicine and Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaomin Yu
- Department of Emergency Medicine, West China Hospital, Sichuan University, West China School of Nursing, Sichuan University, Chengdu, China
- Institute of Disaster Medicine, Sichuan University, Chengdu, China
- Nursing Key Laboratory of Sichuan Province, West China Hospital, Chengdu, China
| | - Tao Cheng
- Department of Emergency Medicine and Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Bofu Liu
- Department of Emergency Medicine and Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
15
|
Gigliotti BJ, Brooks JA, Wirth LJ. Fundamentals and recent advances in the evaluation and management of medullary thyroid carcinoma. Mol Cell Endocrinol 2024; 592:112295. [PMID: 38871174 DOI: 10.1016/j.mce.2024.112295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 05/29/2024] [Accepted: 06/02/2024] [Indexed: 06/15/2024]
Abstract
Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are sporadic, although MTC exhibits a high degree of heritability as part of the multiple endocrine neoplasia syndromes. REarranged during Transfection (RET) mutations are the primary oncogenic drivers and advances in molecular profiling have revealed that MTC is enriched in druggable alterations. Surgery at an early stage is the only chance for cure, but many patients present with or develop metastases. C-cell-specific calcitonin trajectory and structural doubling times are critical biomarkers to inform prognosis, extent of surgery, likelihood of residual disease, and need for additional therapy. Recent advances in the role of active surveillance, regionally directed therapies for localized disease, and systemic therapy with multi-kinase and RET-specific inhibitors for progressive/metastatic disease have significantly improved outcomes for patients with MTC.
Collapse
Affiliation(s)
| | - Jennifer A Brooks
- Department of Otolaryngology Head & Neck Surgery, University of Rochester, Rochester, NY, USA.
| | - Lori J Wirth
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
16
|
Pitoia F, Trimboli P, Abelleira E. Primary resistance to selpercatinib in a patient with advanced medullary thyroid cancer. Endocrine 2024; 86:109-113. [PMID: 38801596 DOI: 10.1007/s12020-024-03890-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 05/20/2024] [Indexed: 05/29/2024]
Abstract
Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation.
Collapse
Affiliation(s)
- Fabian Pitoia
- Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina.
| | - Pierpaolo Trimboli
- Servizio di Endocrinologia e Diabetologia, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland
- Facoltà di Scienze Biomediche, Università della Svizzera Italiana (USI), Lugano, Switzerland
| | - Erika Abelleira
- Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina
| |
Collapse
|
17
|
Zhang Y, Zheng WH, Zhou SH, Gu JL, Yu Q, Zhu YZ, Yan YJ, Zhu Z, Shang JB. Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives. Cell Commun Signal 2024; 22:460. [PMID: 39342195 PMCID: PMC11439284 DOI: 10.1186/s12964-024-01837-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1-2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15-20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10-40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.
Collapse
Affiliation(s)
- Ying Zhang
- Department of Thyroid Surgery, Zhejiang Cancer Hospital, No. 1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Wei-Hui Zheng
- Department of Thyroid Surgery, Zhejiang Cancer Hospital, No. 1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Shi-Hong Zhou
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jia-Lei Gu
- Department of Thyroid Surgery, Zhejiang Cancer Hospital, No. 1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Malignant Tumor, Hangzhou, Zhejiang, China
| | - Qing Yu
- Department of Thyroid Surgery, Zhejiang Cancer Hospital, No. 1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yi-Zhou Zhu
- Department of Thyroid Surgery, Zhejiang Cancer Hospital, No. 1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yu-Jie Yan
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Zhi Zhu
- The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory of Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
| | - Jin-Biao Shang
- Department of Thyroid Surgery, Zhejiang Cancer Hospital, No. 1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China.
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Clinical Research Center for Malignant Tumor, Hangzhou, Zhejiang, China.
| |
Collapse
|
18
|
Huang Q, Ding C, Wang W, Yang L, Wu Y, Zeng W, Li Z, Shi Z, Mei L, Zeng X, Zhao Y, Chen H. An "AND" logic gate-based supramolecular therapeutic nanoplatform for combatting drug-resistant non-small cell lung cancer. SCIENCE ADVANCES 2024; 10:eadp9071. [PMID: 39321294 PMCID: PMC11423878 DOI: 10.1126/sciadv.adp9071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 08/20/2024] [Indexed: 09/27/2024]
Abstract
Despite targeted therapies like epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), non-small cell lung cancer (NSCLC) remains a clinical challenge due to drug resistance hampering their efficacy. Here, we designed an "AND" logic gate-based supramolecular therapeutic platform (HA-BPY-GEF-NPs) for the treatment of EGFR-TKI resistant NSCLC. This system integrates both internal and external stimuli-responsive mechanisms that need to be activated in a preset sequence, enabling it to precisely control drug release behavior for enhancing therapeutic precision. By programming the system to respond to sequential near-infrared (NIR) irradiation and enzyme (cathepsin B) inputs, the release of gefitinib is effectively confined to the tumor region. Moreover, the NIR irradiation induces reactive oxygen species production, suppressing tumor growth and inhibiting bypass signaling pathways. The designed drug delivery system offers a highly controlled and targeted therapeutic approach, effectively inhibiting tumor growth, suppressing bypass signaling pathways, and overcoming EGFR-TKI resistance, thus offering a potential solution for maximizing therapeutic benefits.
Collapse
Affiliation(s)
- Qili Huang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
| | - Chendi Ding
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, P. R. China
- School of Chemistry, Chemical Engineering, and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
| | - Wenyan Wang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
| | - Li Yang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
| | - Yinglong Wu
- School of Chemistry, Chemical Engineering, and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
| | - Wenfeng Zeng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
| | - Zimu Li
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
- School of Chemistry, Chemical Engineering, and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
| | - Zhaoqing Shi
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, P. R. China
| | - Lin Mei
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, P. R. China
| | - Xiaowei Zeng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
| | - Yanli Zhao
- School of Chemistry, Chemical Engineering, and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
| | - Hongzhong Chen
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
| |
Collapse
|
19
|
Qiu D, Zhang XH, Wang Y, Chen C. Case report: Intrapleural plus systemic Tislelizumab injection combined chemotherapy in RET gene fusion-positive lung adenocarcinoma presenting refractory malignant pleural effusion. Front Oncol 2024; 14:1404173. [PMID: 39372862 PMCID: PMC11449677 DOI: 10.3389/fonc.2024.1404173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 08/21/2024] [Indexed: 10/08/2024] Open
Abstract
RET fusions were discovered in non-small cell lung cancer (NSCLC), and the efficacy of RET-targeted treatment in these patients has been previously established. However, patients with required resistance to RET-TKIs have limited treatment options. Herein, we describe a case of critical and advanced lung adenocarcinoma harboring RET fusion. Despite a significant response to Prasetinib previously, the patient developed refractory malignant pleural effusion after 24 months of treatment. He was treated simultaneously with intrapleural plus systemic Tislelizumab injection combined chemotherapy, thereby achieving an excellent clinical benefit maintaining control of pleural effusion for over 6 months. Hence, we would like to discuss intrapleural immunotherapy as an additional treatment method in refractory malignant pleural effusion while demonstrating good treatment tolerance.
Collapse
Affiliation(s)
| | | | | | - Cheng Chen
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
20
|
Maturi A, Sastry KNV, Kumar S, Pogaku V, Kwon HJ, Ahn SM, Kim MH. Side Chain Investigation of Imidazopyridazine as a Hinge Binder for Targeting Actionable Mutations of RET Kinase. ACS Med Chem Lett 2024; 15:1566-1574. [PMID: 39291010 PMCID: PMC11403754 DOI: 10.1021/acsmedchemlett.4c00287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/19/2024] Open
Abstract
Actionable mutations of RET kinase have been identified as oncogenic drivers of solid tumors, including thyroid cancer, metastatic colorectal cancer, and nonsmall cell lung cancer. Although multikinase inhibitors and RET selective inhibitors are used to treat patients with RET alterations, there is insufficient research addressing certain issues: which actionable mutations arise from these therapies, how to improve the clinical response rate to RET inhibitors, and how to design new inhibitors to overcome drug resistance. Therefore, the development of sophisticated tool compounds is required to investigate the molecular mechanisms of actionable mutations and to develop breakthrough therapeutics for different RET alterations. Herein, we present our investigation into the side chains of imidazopyridazine hinge binders that are capable of inducing protein-ligand interaction patterns from the gatekeeper to the waterfront regions. Extending the substituents at the second and sixth positions enhanced the IC50 up to < 0.5 nM for diverse RET alterations.
Collapse
Affiliation(s)
- Arunkranthi Maturi
- Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Kasinathuni Naga Visweswara Sastry
- Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Surendra Kumar
- Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Vinay Pogaku
- Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Republic of Korea
| | | | - Sung-Min Ahn
- Gachon Institute of Genome Medicine and Sciences, Gachon University Gil Medical Center, Incheon 21936, Republic of Korea
- Immunoforge, Seoul 08591, Republic of Korea
| | - Mi-Hyun Kim
- Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Republic of Korea
| |
Collapse
|
21
|
Chen MF, Repetto M, Wilhelm C, Drilon A. RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future. Drugs 2024; 84:1035-1053. [PMID: 38997570 PMCID: PMC11977511 DOI: 10.1007/s40265-024-02040-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2024] [Indexed: 07/14/2024]
Abstract
While activating RET fusions are identified in various cancers, lung cancer represents the most common RET fusion-positive tumor. The clinical drug development of RET inhibitors in RET fusion-positive lung cancers naturally began after RET fusions were first identified in patient tumor samples in 2011, and thereafter paralleled drug development in RET fusion-positive thyroid cancers. Multikinase inhibitors were initially tested with limited efficacy and substantial toxicity. RET inhibitors were then designed with improved selectivity, central nervous system penetrance, and activity against RET fusions and most RET mutations, including resistance mutations. Owing their success to these rationally designed features, the first-generation selective RET tyrosine kinase inhibitors (TKIs) had higher response rates, more durable disease control, and an improved safety profile compared to the multikinase inhibitors. This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers.
Collapse
Affiliation(s)
- Monica F Chen
- Thoracic Oncology, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA
- Early Drug Development Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Matteo Repetto
- Early Drug Development Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Clare Wilhelm
- Thoracic Oncology, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA
- Early Drug Development Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Alexander Drilon
- Thoracic Oncology, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
- Early Drug Development Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
| |
Collapse
|
22
|
Ou X, Gao G, Habaz IA, Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm (Beijing) 2024; 5:e694. [PMID: 39184861 PMCID: PMC11344283 DOI: 10.1002/mco2.694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 07/24/2024] [Accepted: 07/28/2024] [Indexed: 08/27/2024] Open
Abstract
Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on-target mechanisms and off-target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next-generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual-targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI-targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual-acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI-targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.
Collapse
Affiliation(s)
- Xuejin Ou
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Ge Gao
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
- Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China HospitalSichuan UniversityChengduChina
| | - Inbar A. Habaz
- Department of Biochemistry and Biomedical SciencesMcMaster UniversityHamiltonOntarioCanada
| | - Yongsheng Wang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
| |
Collapse
|
23
|
Zhu Y, Qin J, Wu W, Cai L. Development and validation of a novel high-performance liquid chromatography (HPLC) method for the detection of related substances of pralsetinib, a new anti-lung cancer drug. Front Chem 2024; 12:1450692. [PMID: 39233920 PMCID: PMC11371568 DOI: 10.3389/fchem.2024.1450692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/08/2024] [Indexed: 09/06/2024] Open
Abstract
Background Pralsetinib, a targeted inhibitor of the RET enzyme, plays a critical role in the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) characterized by RET gene fusion mutations following platinum-based chemotherapy. Nevertheless, impurities resulting from the manufacturing and degradation of pralsetinib have the potential to impact its therapeutic effectiveness and safety profile. Methods To address this issue, a liquid chromatography method was developed and validated for the specific identification of pralsetinib and its related impurities. The separation of pralsetinib and its related impurities was achieved via a Waters X Bridge C18 column with dimensions of 4.6 mm × 250 mm and a particle size of 5 μm. Mobile phase A was composed of 20 mmol/L potassium dihydrogen phosphate (KH2PO4) and acetonitrile (ACN) at a volume ratio of 19:1, while mobile phase B consisted solely of ACN, utilizing a gradient elution technique. Detection was performed at a wavelength of 260 nm, with an injection volume of 10 μL and a flow rate of 1.0 mL/min. Results The chromatographic method established in this study was validated according to the ICH Q2 (R1) guidelines. The method demonstrated excellent linearity over a specific concentration range (imp-A: 0.035-10.21 μg/mL; imp-B: 0.09-10.16 μg/mL; imp-C: 0.15-10.19 μg/mL; pralsetinib: 0.04-10.32 μg/mL). Additionally, the method possesses high sensitivity, with detection limits for impurities A, B, C, and pralsetinib of 0.01, 0.03, 0.015, and 0.013 μg/mL, respectively, and quantification limits of 0.035, 0.09, 0.05, and 0.04 μg/mL, respectively. In terms of specificity, stability, repeatability, accuracy, and robustness, the method met the validation acceptance criteria. Overall, the chromatographic technique established in this study can effectively separate pralsetinib and its impurities, providing reliable assurance for the accurate detection and quantification of impurities. Conclusion The chromatographic method developed in this study can be utilized for the detection of pralsetinib and its impurities, offering a crucial reference for research on the quality of pralsetinib.
Collapse
Affiliation(s)
- Yonghong Zhu
- Department of Pharmacy, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), Nantong, Jiangsu, China
| | - Jisu Qin
- Department of Pharmacy, Affiliated Hospital of Nantong University, Pharmacy School of Nantong University, Nantong, China
| | - Wenyi Wu
- Department of Quality Inspection, Sinopharm Holding Nantong Ltd., Nantong, China
| | - Liangliang Cai
- Department of Pharmacy, Affiliated Hospital of Nantong University, Pharmacy School of Nantong University, Nantong, China
| |
Collapse
|
24
|
Spitaleri G, Trillo Aliaga P, Attili I, Del Signore E, Corvaja C, Pellizzari G, Katrini J, Passaro A, de Marinis F. Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: "Shadows and Fogs". Cancers (Basel) 2024; 16:2877. [PMID: 39199650 PMCID: PMC11352804 DOI: 10.3390/cancers16162877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 09/01/2024] Open
Abstract
RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.
Collapse
Affiliation(s)
- Gianluca Spitaleri
- Division of Thoracic Oncology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Pamela Trillo Aliaga
- Division of Thoracic Oncology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Ilaria Attili
- Division of Thoracic Oncology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Ester Del Signore
- Division of Thoracic Oncology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Carla Corvaja
- Division of Thoracic Oncology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Gloria Pellizzari
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Jalissa Katrini
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Filippo de Marinis
- Division of Thoracic Oncology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| |
Collapse
|
25
|
Izumi M, Costa DB, Kobayashi SS. Targeting of drug-tolerant persister cells as an approach to counter drug resistance in non-small cell lung cancer. Lung Cancer 2024; 194:107885. [PMID: 39002493 PMCID: PMC11305904 DOI: 10.1016/j.lungcan.2024.107885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/02/2024] [Accepted: 07/05/2024] [Indexed: 07/15/2024]
Abstract
The advent of targeted therapies revolutionized treatments of advanced oncogene-driven non-small cell lung cancer (NSCLC). Nonetheless, despite initial dramatic responses, development of drug resistance is inevitable. Although mechanisms underlying acquired resistance, such as on-target mutations, bypass pathways, or lineage transformation, have been described, overcoming drug resistance remains challenging. Recent evidence suggests that drug-tolerant persister (DTP) cells, which are tumor cells tolerant to initial drug exposure, give rise to cells that acquire drug resistance. Thus, the possibility of eradicating cancer by targeting DTP cells is under investigation, and various strategies are proposed. Here, we review overall features of DTP cells, current efforts to define DTP markers, and potential therapeutic strategies to target and eradicate DTP cells in oncogene-driven NSCLC. We also discuss future challenges in the field.
Collapse
Affiliation(s)
- Motohiro Izumi
- Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Daniel B Costa
- Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Susumu S Kobayashi
- Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| |
Collapse
|
26
|
Shiba-Ishii A, Isagawa T, Shiozawa T, Mato N, Nakagawa T, Takada Y, Hirai K, Hong J, Saitoh A, Takeda N, Niki T, Murakami Y, Matsubara D. Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167249. [PMID: 38768929 DOI: 10.1016/j.bbadis.2024.167249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/11/2024] [Accepted: 05/15/2024] [Indexed: 05/22/2024]
Abstract
RET fusion is an oncogenic driver in 1-2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.
Collapse
MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Proto-Oncogene Proteins c-ret/antagonists & inhibitors
- Proto-Oncogene Proteins c-ret/genetics
- Proto-Oncogene Proteins c-ret/metabolism
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Lung Neoplasms/drug therapy
- Lung Neoplasms/pathology
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Mitochondria/metabolism
- Mitochondria/drug effects
- Piperidines/pharmacology
- Piperidines/therapeutic use
- Protein Kinase Inhibitors/therapeutic use
- Protein Kinase Inhibitors/pharmacology
- Cell Line, Tumor
- Quinazolines/pharmacology
- Quinazolines/therapeutic use
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Transcription Factors/antagonists & inhibitors
- Signal Transduction/drug effects
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Oncogene Proteins, Fusion/antagonists & inhibitors
- DNA Helicases/genetics
- DNA Helicases/metabolism
- DNA Helicases/antagonists & inhibitors
- Cytoskeletal Proteins
Collapse
Affiliation(s)
- Aya Shiba-Ishii
- Department of Diagnostic Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Takayuki Isagawa
- Center for Data Science, Jichi Medical University, Tochigi, Japan
| | - Toshihiro Shiozawa
- Department of Respiratory Medicine, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Naoko Mato
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Ibaraki, Japan
| | - Tomoki Nakagawa
- Department of Pathology, University of Tsukuba Hospital, Ibaraki, Japan
| | - Yurika Takada
- Department of Diagnostic Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kanon Hirai
- Department of Diagnostic Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Jeongmin Hong
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Anri Saitoh
- Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Norihiko Takeda
- Division of Cardiology and Metabolism, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Toshiro Niki
- Department of Pathology, Jichi Medical University, Tochigi, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Daisuke Matsubara
- Department of Diagnostic Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
| |
Collapse
|
27
|
Deschler-Baier B, Krebs M, Kroiss M, Chatterjee M, Gundel D, Kestler C, Kerscher A, Kunzmann V, Appenzeller S, Maurus K, Rosenwald A, Bargou R, Gerhard-Hartmann E, Venkataramani V. Rapid response to selpercatinib in RET fusion positive pancreatic neuroendocrine carcinoma confirmed by smartwatch. NPJ Precis Oncol 2024; 8:167. [PMID: 39085487 PMCID: PMC11291676 DOI: 10.1038/s41698-024-00659-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 07/16/2024] [Indexed: 08/02/2024] Open
Abstract
This case report describes the efficacy of selpercatinib, a selective RET inhibitor, in an unusual case of large-cell neuroendocrine pancreatic carcinoma (LCNEPAC) harboring a CCDC6::RET fusion. A 56-year-old male with a history of multiple lines of systemic therapies exhibited marked clinical amelioration shortly after initiating selpercatinib within the LOXO-RET-17001 study (ClinicalTrials.gov ID: NCT03157128, first posted: 2017-05-17). Data from the patient's smartwatch suggested early efficacy before conventional methods, such as serum tumor markers and CT imaging confirmed the antitumor activity. This case not only underscores the efficacy of selpercatinib in treating RET fusion-positive rare tumors but also highlights the potential of wearable technology in cancer care. In conclusion, the standard readings from commercially available wearable devices can be useful for the monitoring of treatment response to targeted therapy and may serve as digital biomarkers in clinical trials. This approach marks a significant advancement in patient-centric healthcare, leveraging technology to enhance the effectiveness and precision of treatment evaluation.
Collapse
Affiliation(s)
- Barbara Deschler-Baier
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Markus Krebs
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
- Department of Urology and Pediatric Urology, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Matthias Kroiss
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080, Würzburg, Germany
- Department of Internal Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München, 80366, Munich, Germany
| | - Manik Chatterjee
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Daniel Gundel
- Hämatologisch-Onkologische Schwerpunktpraxis Würzburg, 97080, Würzburg, Germany
| | - Christian Kestler
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
- Institute for Diagnostic and Interventional Radiology, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Alexander Kerscher
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Volker Kunzmann
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
- Department of Internal Medicine II, Medical Oncology, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Silke Appenzeller
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Katja Maurus
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
- Institute of Pathology, University of Würzburg, 97080, Würzburg, Germany
| | - Andreas Rosenwald
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
- Institute of Pathology, University of Würzburg, 97080, Würzburg, Germany
| | - Ralf Bargou
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
- Bavarian Cancer Research Center (BZKF), 97080, Würzburg, Germany
| | - Elena Gerhard-Hartmann
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany
- Institute of Pathology, University of Würzburg, 97080, Würzburg, Germany
| | - Vivek Venkataramani
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080, Würzburg, Germany.
| |
Collapse
|
28
|
Cognigni V, Giudice GC, Bozzetti F, Milanese G, Moschini I, Casali M, Mazzaschi G, Tiseo M. Successful treatment with selpercatinib after pralsetinib-related pneumonitis and intracranial failure in a patient with RET-rearranged nonsmall cell lung cancer. Anticancer Drugs 2024; 35:559-562. [PMID: 38453158 PMCID: PMC11078287 DOI: 10.1097/cad.0000000000001590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 02/03/2024] [Indexed: 03/09/2024]
Abstract
Pralsetinib and selpercatinib are two highly potent and selective rearranged during transfection (RET) inhibitors that substantially improved the clinical outcome of patients with RET-rearranged non-small cell lung cancer. Treatment with one RET inhibitor after failure of the other is generally not recommended because of cross-resistance mechanisms. We report the case of a patient affected by metastatic RET-rearranged non-small cell lung cancer who experienced long-lasting disease control with pralsetinib. After 13 months from treatment start, the patient developed recurrent drug-related pneumonitis, requiring temporary interruptions and dose reductions and eventually failing to control the disease. Selpercatinib was then started as an off-label treatment, allowing both clinical and radiological intracranial disease control. Selpercatinib was well-tolerated at full dosage, and no pulmonary event occurred. In our case report, after pralsetinib dose reduction due to pulmonary toxicity, the therapeutic switch to selpercatinib allowed the patient to receive a full-dose treatment, eventually restoring disease control. Our case report and a few literature data suggest that switching from pralsetinib to selpercatinib may represent a therapeutic opportunity, especially for patients with brain metastases.
Collapse
Affiliation(s)
- Valeria Cognigni
- Department of Medical Oncology, Università Politecnica delle Marche, Ancona
| | | | - Francesca Bozzetti
- Department of Medicine and Surgery, University of Parma
- Neuroradiology Unit
| | - Gianluca Milanese
- Department of Medicine and Surgery, University of Parma
- Radiology Unit, University Hospital of Parma, Parma
| | | | - Miriam Casali
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale di Lodi, Lodi, Italy
| | - Giulia Mazzaschi
- Department of Medicine and Surgery, University of Parma
- Medical Oncology Unit
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma
- Medical Oncology Unit
| |
Collapse
|
29
|
Brandenburg T, Kroiß M. [Thyroid carcinomas: the role of systemic therapies in internal medicine]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2024; 65:642-655. [PMID: 38900279 DOI: 10.1007/s00108-024-01728-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/15/2024] [Indexed: 06/21/2024]
Abstract
The molecular pathogenesis of thyroid carcinoma is well studied and of importance for the treatment of advanced stages. Differentiated, poorly differentiated and anaplastic carcinomas originate in the follicular cells, while medullary carcinomas derive from the C‑cells. The prognosis of differentiated thyroid carcinoma is generally very favourable after surgery and radioiodine therapy. Where tumours progress and lose the ability to enrich iodine, curative treatment is usually not possible. A strategy of watchful waiting is often appropriate. Activating mutations in BRAF or gene fusions of RET and NTRK provide opportunities for targeted therapies. These may be applied with the aim of restoring iodine uptake (redifferentiation). In the absence of molecular therapy targets, multityrosine kinase inhibitors (MKI) are the therapy of choice. If anaplastic thyroid carcinoma is suspected, rapid diagnostic workup including molecular pathology is warranted. Surgery where possible and radiochemotherapy are essential components of therapy. In the presence of a BRAF mutation, inhibition of BRAF and MEK is effective, even if it is not approved in Germany. Where molecular targets are lacking, combination therapy with the MKI lenvatinib and immune checkpoint inhibition is highly effective. Mutations in RET are present in the vast majority of cases of medullary thyroid carcinoma. In aggressive advanced disease, selective RET inhibition has recently been approved as first-line therapy and often leads to an objective response and long-lasting disease stabilisation. In summary, thyroid carcinomas are among the tumour entities for which molecularly targeted therapies can be used most frequently. The involvement of specialised centres is advisable.
Collapse
Affiliation(s)
- Tim Brandenburg
- Klinik für Endokrinologie, Diabetologie und Stoffwechsel, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland.
- Endokrines Tumorzentrum am Westdeutschen Tumorzentrum (WTZ), Universitätsklinikum Essen, Member of Endo-ERN and EURACAN, Universität Duisburg-Essen, Duisburg-Essen, Deutschland.
| | - Matthias Kroiß
- Medizinische Klinik IV, Universitätsklinikum, Member of Endo-ERN and EURACAN, Ludwig-Maximilians-Universität München, Ziemssenstr. 5, 80336, München, Deutschland.
- Comprehensive Cancer Center München, Ludwig-Maximilians-Universität München, München, Deutschland.
- Bayerisches Zentrum für Krebsforschung, München, Deutschland.
| |
Collapse
|
30
|
Dessai A, Nayak UY, Nayak Y. Precision nanomedicine to treat non-small cell lung cancer. Life Sci 2024; 346:122614. [PMID: 38604287 DOI: 10.1016/j.lfs.2024.122614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/30/2024] [Accepted: 04/03/2024] [Indexed: 04/13/2024]
Abstract
Lung cancer is a major cause of death worldwide, being often detected at a later stage due to the non-appearance of early symptoms. Therefore, specificity of the treatment is of utmost importance for its effective treatment. Precision medicine is a personalized therapy based on the genomics of the patient to design a suitable drug approach. Genetic mutations render the tumor resistant to specific mutations and the therapy is in vain even though correct medications are prescribed. Therefore, Precision medicine needs to be explored for the treatment of Non-small cell lung cancer (NSCLC). Nanoparticles are widely explored to give personalized interventions to treat lung cancer due to their various advantages like the ability to reach cancer cells, enhanced permeation through tissues, specificity, increased bioavailability, etc. Various nanoparticles (NPs) including gold nanoparticles, carbon nanotubes, aptamer-based NPs etc. were conjugated with biomarkers/diagnostic agents specific to cancer type and were delivered. Various biomarker genes have been identified through precision techniques for the diagnosis and treatment of NSCLC like EGFR, RET, KRAS, ALK, ROS-1, NTRK-1, etc. By incorporating of drug with the nanoparticle through bioconjugation, the specificity of the treatment can be enhanced with this revolutionary treatment. Additionally, integration of theranostic cargos in the nanoparticle would allow diagnosis as well as treatment by targeting the site of disease progression. Therefore, to target NSCLC effectively precision nanomedicine has been adopted in recent times. Here, we present different nanoparticles that are used as precision nanomedicine and their effectiveness against NSCLC disease.
Collapse
Affiliation(s)
- Akanksha Dessai
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Usha Yogendra Nayak
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
| | - Yogendra Nayak
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| |
Collapse
|
31
|
Kumar V, Yochum ZA, Devadassan P, Huang EHB, Miller E, Baruwal R, Rumde PH, GaitherDavis AL, Stabile LP, Burns TF. TWIST1 is a critical downstream target of the HGF/MET pathway and is required for MET driven acquired resistance in oncogene driven lung cancer. Oncogene 2024; 43:1431-1444. [PMID: 38485737 PMCID: PMC11068584 DOI: 10.1038/s41388-024-02987-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/15/2024] [Accepted: 02/19/2024] [Indexed: 03/19/2024]
Abstract
MET amplification/mutations are important targetable oncogenic drivers in NSCLC, however, acquired resistance is inevitable and the majority of patients with targetable MET alterations fail to respond to MET tyrosine kinase inhibitors (TKIs). Furthermore, MET amplification is among the most common mediators of TKI resistance. As such, novel therapies to target MET pathway and overcome MET TKI resistance are clearly needed. Here we show that the epithelial-mesenchymal transition (EMT) transcription factor, TWIST1 is a key downstream mediator of HGF/MET induced resistance through suppression of p27 and targeting TWIST1 can overcome resistance. We found that TWIST1 is overexpressed at the time of TKI resistance in multiple MET-dependent TKI acquired resistance PDX models. We have shown for the first time that MET directly stabilized the TWIST protein leading to TKI resistance and that TWIST1 was required for MET-driven lung tumorigenesis as well as could induce MET TKI resistance when overexpressed. TWIST1 mediated MET TKI resistance through suppression of p27 expression and genetic or pharmacologic inhibition of TWIST1 overcame TKI resistance in vitro and in vivo. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome resistance in MET-driven NSCLC as well as in other oncogene driven subtypes in which MET amplification is the resistance mechanism.
Collapse
Affiliation(s)
- Vinod Kumar
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Zachary A Yochum
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Medicine, Medical Oncology, Yale School of Medicine, New Haven, CT, USA
| | - Princey Devadassan
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Eric H-B Huang
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Ethan Miller
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Roja Baruwal
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Purva H Rumde
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Autumn L GaitherDavis
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Laura P Stabile
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Timothy F Burns
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| |
Collapse
|
32
|
Jabbarzadeh Kaboli P, Chen HF, Babaeizad A, Roustai Geraylow K, Yamaguchi H, Hung MC. Unlocking c-MET: A comprehensive journey into targeted therapies for breast cancer. Cancer Lett 2024; 588:216780. [PMID: 38462033 DOI: 10.1016/j.canlet.2024.216780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/18/2024] [Accepted: 02/29/2024] [Indexed: 03/12/2024]
Abstract
Breast cancer is the most common malignancy among women, posing a formidable health challenge worldwide. In this complex landscape, the c-MET (cellular-mesenchymal epithelial transition factor) receptor tyrosine kinase (RTK), also recognized as the hepatocyte growth factor (HGF) receptor (HGFR), emerges as a prominent protagonist, displaying overexpression in nearly 50% of breast cancer cases. Activation of c-MET by its ligand, HGF, secreted by neighboring mesenchymal cells, contributes to a cascade of tumorigenic processes, including cell proliferation, metastasis, angiogenesis, and immunosuppression. While c-MET inhibitors such as crizotinib, capmatinib, tepotinib and cabozantinib have garnered FDA approval for non-small cell lung cancer (NSCLC), their potential within breast cancer therapy is still undetermined. This comprehensive review embarks on a journey through structural biology, multifaceted functions, and intricate signaling pathways orchestrated by c-MET across cancer types. Furthermore, we highlight the pivotal role of c-MET-targeted therapies in breast cancer, offering a clinical perspective on this promising avenue of intervention. In this pursuit, we strive to unravel the potential of c-MET as a beacon of hope in the fight against breast cancer, unveiling new horizons for therapeutic innovation.
Collapse
Affiliation(s)
- Parham Jabbarzadeh Kaboli
- Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, 406, Taiwan
| | - Hsiao-Fan Chen
- Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, 406, Taiwan
| | - Ali Babaeizad
- Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Hirohito Yamaguchi
- Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, 406, Taiwan
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, 406, Taiwan; Department of Biotechnology, Asia University, Taichung, 413, Taiwan.
| |
Collapse
|
33
|
Xiang Y, Liu X, Wang Y, Zheng D, Meng Q, Jiang L, Yang S, Zhang S, Zhang X, Liu Y, Wang B. Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges. Front Immunol 2024; 15:1366260. [PMID: 38655260 PMCID: PMC11035781 DOI: 10.3389/fimmu.2024.1366260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/18/2024] [Indexed: 04/26/2024] Open
Abstract
Resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) is a significant challenge in the treatment of this disease. The mechanisms of resistance are multifactorial and include molecular target alterations and activation of alternative pathways, tumor heterogeneity and tumor microenvironment change, immune evasion, and immunosuppression. Promising strategies for overcoming resistance include the development of combination therapies, understanding the resistance mechanisms to better use novel drug targets, the identification of biomarkers, the modulation of the tumor microenvironment and so on. Ongoing research into the mechanisms of resistance and the development of new therapeutic approaches hold great promise for improving outcomes for patients with NSCLC. Here, we summarize diverse mechanisms driving resistance to targeted therapy and immunotherapy in NSCLC and the latest potential and promising strategies to overcome the resistance to help patients who suffer from NSCLC.
Collapse
Affiliation(s)
- Yuchu Xiang
- West China Hospital of Sichuan University, Sichuan University, Chengdu, China
| | - Xudong Liu
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Yifan Wang
- State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai, China
| | - Dawei Zheng
- The College of Life Science, Sichuan University, Chengdu, China
| | - Qiuxing Meng
- Department of Laboratory Medicine, Liuzhou People’s Hospital, Liuzhou, China
- Guangxi Health Commission Key Laboratory of Clinical Biotechnology (Liuzhou People’s Hospital), Liuzhou, China
| | - Lingling Jiang
- Guangxi Medical University Cancer Hospital, Nanning, China
| | - Sha Yang
- Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, China
| | - Sijia Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zhang
- Zhongshan Hospital of Fudan University, Xiamen, Fujian, China
| | - Yan Liu
- Department of Organ Transplantation, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| | - Bo Wang
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| |
Collapse
|
34
|
Nishikawa G, Klein MA. Targeting RET alterations in non-small cell lung cancer. Curr Probl Cancer 2024; 49:101074. [PMID: 38494387 DOI: 10.1016/j.currproblcancer.2024.101074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/12/2024] [Accepted: 02/18/2024] [Indexed: 03/19/2024]
Abstract
Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell lung cancer (NSCLC), RET mutations often manifest as RET fusion genes and are observed in 1-2 % of patients with NSCLC. In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. While first-generation RET inhibitors have become part of the standard of care for RET-fusion positive NSCLC, a new challenge has emerged: acquired resistance to RET inhibitors. RET resistance is a complex phenomenon that can manifest as either on-target or off-target resistance. Numerous studies have been conducted to identify the mechanisms behind this resistance. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.
Collapse
Affiliation(s)
- Go Nishikawa
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Mark A Klein
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Hematology/Oncology Section, Primary Care Service Line, Minneapolis VA Health Care System, Minneapolis, MN, USA.
| |
Collapse
|
35
|
Hamidi S, Hu MI. RET kinase inhibitors for the treatment of RET-altered thyroid cancers: Current knowledge and future directions. ANNALES D'ENDOCRINOLOGIE 2024; 85:118-126. [PMID: 38342224 DOI: 10.1016/j.ando.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
RET gain-of-function mutations are the most common drivers in medullary thyroid carcinoma, while RET fusions are identified in 5-10% of papillary thyroid carcinomas. Thus, RET plays a major role in the tumorigenesis of thyroid neoplasia, making it a valuable therapeutic target. Over a decade ago, multikinase inhibitors (MKIs) were first shown to have variable degrees of anti-RET activity. Despite some clinical efficacy in RET-altered thyroid cancers, significant off-target activity of MKIs led to marked toxicities limiting their use. More recently, two potent, highly selective RET inhibitors, selpercatinib and pralsetinib, were shown to have notable efficacy in RET-altered cancers, associated with more tolerable side effect profiles than those of MKIs. However, these treatments are non-curative, and emerging evidence suggests that patients who progress on therapy acquire mutations conferring drug resistance. Thus, the quest for a more definitive treatment for advanced, RET-altered thyroid cancers continues. This year we celebrate the 30th anniversary of the association of germline mutations of the RET proto-oncogene with the multiple endocrine neoplasia (MEN) type 2 syndromes. In this timely review, we summarize the current state-of-the-art treatment strategies for RET-altered thyroid cancers, their limitations, as well as future therapeutic avenues.
Collapse
Affiliation(s)
- Sarah Hamidi
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston, TX, 77030, USA.
| | - Mimi I Hu
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston, TX, 77030, USA
| |
Collapse
|
36
|
Subbiah V, Gouda MA, Iorgulescu JB, Dadu R, Patel K, Sherman S, Cabanillas M, Hu M, Castellanos LE, Amini B, Meric-Bernstam F, Shen T, Wu J. Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer. NPJ Precis Oncol 2024; 8:62. [PMID: 38438731 PMCID: PMC10912412 DOI: 10.1038/s41698-024-00563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 02/23/2024] [Indexed: 03/06/2024] Open
Abstract
Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.
Collapse
Affiliation(s)
- Vivek Subbiah
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Sarah Cannon Research Institute, Nashville, TN, USA.
| | - Mohamed A Gouda
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Bryan Iorgulescu
- Molecular Diagnostics Laboratory, Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ramona Dadu
- Department of Endocrine Neoplasia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keyur Patel
- Molecular Diagnostics Laboratory, Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Steven Sherman
- Department of Endocrine Neoplasia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria Cabanillas
- Department of Endocrine Neoplasia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mimi Hu
- Department of Endocrine Neoplasia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Luz E Castellanos
- Department of Endocrine Neoplasia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Behrang Amini
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tao Shen
- Peggy and Charles Stephenson Cancer Center and Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jie Wu
- Peggy and Charles Stephenson Cancer Center and Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| |
Collapse
|
37
|
Friedlaender A, Perol M, Banna GL, Parikh K, Addeo A. Oncogenic alterations in advanced NSCLC: a molecular super-highway. Biomark Res 2024; 12:24. [PMID: 38347643 PMCID: PMC10863183 DOI: 10.1186/s40364-024-00566-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/17/2024] [Indexed: 02/15/2024] Open
Abstract
Lung cancer ranks among the most common cancers world-wide and is the first cancer-related cause of death. The classification of lung cancer has evolved tremendously over the past two decades. Today, non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, comprises a multitude of molecular oncogenic subsets that change both the prognosis and management of disease.Since the first targeted oncogenic alteration identified in 2004, with the epidermal growth factor receptor (EGFR), there has been unprecedented progress in identifying and targeting new molecular alterations. Almost two decades of experience have allowed scientists to elucidate the biological function of oncogenic drivers and understand and often overcome the molecular basis of acquired resistance mechanisms. Today, targetable molecular alterations are identified in approximately 60% of lung adenocarcinoma patients in Western populations and 80% among Asian populations. Oncogenic drivers are largely enriched among non-smokers, east Asians, and younger patients, though each alteration has its own patient phenotype.The current landscape of druggable molecular targets includes EGFR, anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirstin rat sarcoma virus (KRAS), human epidermal receptor 2 (HER2), c-MET proto-oncogene (MET), neurotrophic receptor tyrosine kinase (NTRK), rearranged during transfection (RET), neuregulin 1 (NRG1). In addition to these known targets, others including Phosphoinositide 3-kinases (PI3K) and fibroblast growth factor receptor (FGFR) have garnered significant attention and are the subject of numerous ongoing trials.In this era of personalized, precision medicine, it is of paramount importance to identify known or potential oncogenic drivers in each patient. The development of targeted therapy is mirrored by diagnostic progress. Next generation sequencing offers high-throughput, speed and breadth to identify molecular alterations in entire genomes or targeted regions of DNA or RNA. It is the basis for the identification of the majority of current druggable alterations and offers a unique window into novel alterations, and de novo and acquired resistance mechanisms.In this review, we discuss the diagnostic approach in advanced NSCLC, focusing on current oncogenic driver alterations, through their pathophysiology, management, and future perspectives. We also explore the shortcomings and hurdles encountered in this rapidly evolving field.
Collapse
Affiliation(s)
- Alex Friedlaender
- Clinique Générale Beaulieu, Geneva, Switzerland
- Oncology Department, University Hospital Geneva, Rue Gentil Perret 4. 1205, Geneva, Switzerland
| | - Maurice Perol
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Giuseppe Luigi Banna
- Portsmouth Hospitals University NHS Trust, Portsmouth, UK
- Faculty of Science and Health, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | | | - Alfredo Addeo
- Oncology Department, University Hospital Geneva, Rue Gentil Perret 4. 1205, Geneva, Switzerland.
| |
Collapse
|
38
|
Lu X, Yu R, Li Z, Yang M, Dai J, Liu M. JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers. Cancer Lett 2024; 582:216517. [PMID: 38101609 DOI: 10.1016/j.canlet.2023.216517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/13/2023] [Accepted: 11/23/2023] [Indexed: 12/17/2023]
Abstract
Src homology 2 domain-containing phosphatase (SHP2) is a non-receptor protein phosphatase that transduces signals from upstream receptor tyrosine kinases (RTKs)/non-RTKs to Ras/MAPK pathway. Accumulating studies indicated that SHP2 is a critical mediator of resistance to current targeted therapies in multiple cancers. Here, we reported a novel SHP2 allosteric inhibitor JC-010a, which was highly selective to SHP2 and bound at the "tunnel" allosteric site of SHP2. The effect of JC-010a on combating RTK/non-RTK or MAPK inhibitors-induced acquired resistance was explored. Our study demonstrated that JC-010a monotherapy significantly inhibited the proliferation of cancer cells with different oncogenic drivers via inhibiting signaling through SHP2. Importantly, JC-010a abolished acquired resistance induced by targeted therapies: in KRAS-mutant cancers, JC-010a abrogated selumetinib-induced adaptive resistance mediated by RTK/SHP2; in BCR-ABL-driven leukemia cells, we demonstrated JC-010a inhibited BCR-ABL T315I mutation-mediated imatinib resistance and proposed a novel mechanism of JC-010a involving the disrupted co-interaction of SHP2, BCR-ABL, and Hsp90; in non-small cell lung cancer (NSCLC) cells, JC-010a inhibited both EGFR T790M/C797S mutation and alternate RTK-driven resistance to gefitinib or osimertinib; importantly, we first proposed a novel potential therapeutic strategy for RET-rearranged cancer, we confirmed that JC-010a monotherapy inhibited cell resistance to BLU-667, and JC-010a/BLU-667 combination prolonged anticancer response both in vivo and in vitro cancer models by inhibiting the alternate MET activation-induced RAS/MAPK reactivation, thereby promoting cancer cell apoptosis. These findings suggested that JC-010a was a novel selective SHP2 allosteric inhibitor, and combing JC-010a with current targeted therapy agents provided a promising therapeutic approach for clinical resistant cancers.
Collapse
Affiliation(s)
- Xuxiu Lu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China
| | - Rilei Yu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China
| | - Zhen Li
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Mengke Yang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Jiajia Dai
- Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Ming Liu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
| |
Collapse
|
39
|
Patil T, Staley A, Nie Y, Sakamoto M, Stalker M, Jurica JM, Koehler K, Cass A, Kuykendall H, Schmitt E, Filar E, Reventaite E, Davies KD, Nijmeh H, Haag M, Yoder BA, Bunn PA, Schenk EL, Aisner DL, Iams WT, Marmarelis ME, Camidge DR. The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC. JTO Clin Res Rep 2024; 5:100637. [PMID: 38361741 PMCID: PMC10867444 DOI: 10.1016/j.jtocrr.2024.100637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/11/2024] [Accepted: 01/14/2024] [Indexed: 02/17/2024] Open
Abstract
Introduction Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.
Collapse
Affiliation(s)
- Tejas Patil
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Alyse Staley
- University of Colorado Cancer Center Biostatistics Core, University of Colorado School of Medicine, Aurora, Colorado
| | - Yunan Nie
- Department of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut
| | - Mandy Sakamoto
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Margaret Stalker
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - James M. Jurica
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Kenna Koehler
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Amanda Cass
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Halle Kuykendall
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Emily Schmitt
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Emma Filar
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Evelina Reventaite
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Kurt D. Davies
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Hala Nijmeh
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Mary Haag
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Benjamin A. Yoder
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Paul A. Bunn
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Erin L. Schenk
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Dara L. Aisner
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Wade T. Iams
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Melina E. Marmarelis
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - D. Ross Camidge
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| |
Collapse
|
40
|
Russo GL, Bironzo P, Bennati C, Bonanno L, Catino A, Metro G, Petrini I, Russano M, Passaro A. Clinical evidence and adverse event management update of patients with RET- rearranged advanced non-small-cell lung cancer (NSCLC) treated with pralsetinib. Crit Rev Oncol Hematol 2024; 194:104243. [PMID: 38135019 DOI: 10.1016/j.critrevonc.2023.104243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/12/2023] [Accepted: 12/17/2023] [Indexed: 12/24/2023] Open
Abstract
Current non-small cell lung cancer (NSCLC) management relies on genome-driven precision oncology thus shifting treatment paradigm towards biomarker-guided tumor-agnostic approaches. Recently, rearranged during transfection (RET) has been endorsed as tissue-agnostic target with sensitivity to RET inhibition. There are currently two selective RET tyrosine kinase inhibitors, pralsetinib and selpercatinib. The recent introduction of pralsetinib in the treatment algorithm of RET-rearranged tumor along with the mounting clinical evidence of pralsetinib durable activity from both randomized and observational studies holds the potential to disclose new avenues in the management of RET fusion positive NSCLC patients. Our narrative review aims to discuss the available clinical evidence on pralsetinib efficacy, particularly on brain metastases, and tolerability profile. In addition, our work explores the relevance of detecting RET fusions upfront in the disease history of patients with NSCLC.
Collapse
Affiliation(s)
- Giuseppe Lo Russo
- Medical Oncology Department, Thoracic Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Bironzo
- Department of Oncology, University of Torino, Ospedale San Luigi Gonzaga, Orbassano, TO, Italy
| | - Chiara Bennati
- Department of Onco-Hematology, AUSL della Romagna, Ravenna, Italy
| | - Laura Bonanno
- Medical Oncology 2, Istituto Oncologico Veneto IOV IRCCS, Padova, Italy
| | - Annamaria Catino
- Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Giulio Metro
- Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera Perugia, Italy
| | - Iacopo Petrini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Marco Russano
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milano, Italy.
| |
Collapse
|
41
|
Wan R, Li W, Wang Z, Zhong J, Lin L, Duan J, Wang J. Real-world outcomes of chemoimmunotherapy and selective RET inhibitors in Chinese patients with RET fusion-positive non-small cell lung cancer. Heliyon 2024; 10:e24796. [PMID: 38304763 PMCID: PMC10831772 DOI: 10.1016/j.heliyon.2024.e24796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 01/14/2024] [Accepted: 01/15/2024] [Indexed: 02/03/2024] Open
Abstract
Background Rearranged during transfection (RET) gene fusion is a target for non-small cell lung cancer (NSCLC) treatment, and RET inhibitors are approved for advanced NSCLC. The role of immune checkpoint inhibitors (ICIs) in RET fusion-positive NSCLC remains controversial. This retrospective study analyzed the efficacy of ICIs and RET inhibitors in Chinese patients with RET fusion-positive NSCLC. Methods Data from patients diagnosed with advanced NSCLC harboring RET fusion from Jan 2017 to Sep 2021 were analyzed. Clinicopathological characteristics and outcomes of ICIs and RET inhibitors treatments were collected. Results Seventy-five patients with RET fusion-positive advanced NSCLC were identified. The median age of patients was 57 years, half of the patients were female (50.3%), and most were non-smokers or light smokers (72%). Of the cancer types diagnosed in study patients, the KIF5B-RET fusion subtype accounted for 73.3% (55/75), twelve patients (16%) had CCDC6-RET fusion, and three (4%) had NCOA4-RET fusion. Sixteen patients were treated with ICIs. In previously untreated patients, we observed an objective response rate (ORR) of 71.4% and median progression free survival (PFS) of 7.5 months in seven assessable patients. Of four patients with PD-L1 overexpression (>50%) one received pembrolizumab and the other three patients received pemetrexed, carboplatin, and pembrolizumab or camrelizumab. In these patients, the ORR was 75% and disease control rate was 100%. Fifteen patients received selective RET inhibitors (pralsetinib and selpercatinib), resulting in an ORR of 53.3% (8/15) and median PFS of 10.0 months (95% CI 5.2-14.9). Conclusions ICIs for PD-L overexpression and treatment naive patients offer comparable benefits for RET fusion-positive NSCLC, warranting further investigation.
Collapse
Affiliation(s)
- Rui Wan
- State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Weihua Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhijie Wang
- State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jia Zhong
- State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lin Lin
- State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianchun Duan
- State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jie Wang
- State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| |
Collapse
|
42
|
Yang M, Mandal E, Liu FX, O’Hara RM, Lesher B, Sanborn RE. Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments. Front Oncol 2024; 13:1241402. [PMID: 38273845 PMCID: PMC10808753 DOI: 10.3389/fonc.2023.1241402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 11/27/2023] [Indexed: 01/27/2024] Open
Abstract
Introduction Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC). We reviewed the epidemiology and disease characteristics associated with primary and secondary METamp, as well as the testing procedures used to identify METamp, in advanced NSCLC. Economic and humanistic burdens, and the practice patterns and treatments under investigation for METamp were also examined. Methods Embase and Medline (via ProQuest), ClinicalTrials.gov, and Cochrane Controlled Register of Trials (2015-2022) were systematically searched. Conference abstracts were searched via Embase and conference proceedings websites (2020-2022). The review focused on evidence from the United States; global evidence was included for identified evidence gaps. Results The median rate of primary METamp in NSCLC across the references was 4.8% (n=4 studies) and of secondary METamp (epidermal growth factor receptor [EGFR]-mutant NSCLC) was 15% (n=10). Next-generation sequencing (NGS; n=12) and/or fluorescence in situ hybridization (FISH; n=11) were most frequently used in real-world studies and FISH testing most frequently used in clinical trials (n=9/10). METamp definitions varied among clinical trials using ISH/FISH testing (MET to chromosome 7 centromere ratio of ≥1.8 to ≥3.0; or gene copy number [GCN] ≥5 to ≥10) and among trials using NGS (tissue testing: GCN ≥6; liquid biopsy: MET copy number ≥2.1 to >5). Limited to no data were identified on the economic and humanistic burdens, and real-world treatment of METamp NSCLC. Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines. Conclusion Primary METamp occurs in approximately 5% of NSCLC cases, and secondary METamp in approximately 15% of cases previously treated with an EGFR inhibitor. Variability in testing methods (including ISH/FISH and NGS) and definitions were observed. Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.
Collapse
Affiliation(s)
- Mo Yang
- North America Evidence and Value Development, North America Medical Affairs, EMD Serono, Inc., Rockland, MA, United States, an affiliate of Merck KGaA
| | - Erin Mandal
- Evidence and Access, OPEN Health, Parsippany, NJ, United States
| | - Frank X. Liu
- North America Evidence and Value Development, North America Medical Affairs, EMD Serono, Inc., Rockland, MA, United States, an affiliate of Merck KGaA
| | - Richard M. O’Hara
- North America Evidence and Value Development, North America Medical Affairs, EMD Serono, Inc., Rockland, MA, United States, an affiliate of Merck KGaA
| | - Beth Lesher
- Evidence and Access, OPEN Health, Parsippany, NJ, United States
| | - Rachel E. Sanborn
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States
| |
Collapse
|
43
|
Wu Q, Ellis H, Siravegna G, Michel AG, Norden BL, Fece de la Cruz F, Balasooriya ER, Zhen Y, Silveira VS, Che J, Corcoran RB, Bardeesy N. Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma. Clin Cancer Res 2024; 30:198-208. [PMID: 37843855 PMCID: PMC10767308 DOI: 10.1158/1078-0432.ccr-23-1317] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/18/2023] [Accepted: 10/12/2023] [Indexed: 10/17/2023]
Abstract
PURPOSE FGFR inhibitors are effective in FGFR2-altered cholangiocarcinoma, leading to approval of reversible FGFR inhibitors, pemigatinib and infigratinib, and an irreversible inhibitor, futibatinib. However, acquired resistance develops, limiting clinical benefit. Some mechanisms of resistance have been reported, including secondary FGFR2 kinase domain mutations. Here, we sought to establish the landscape of acquired resistance to FGFR inhibition and to validate findings in model systems. EXPERIMENTAL DESIGN We examined the spectrum of acquired resistance mechanisms detected in circulating tumor DNA or tumor tissue upon disease progression following FGFR inhibitor therapy in 82 FGFR2-altered cholangiocarcinoma patients from 12 published reports. Functional studies of candidate resistance alterations were performed. RESULTS Overall, 49 of 82 patients (60%) had one or more detectable secondary FGFR2 kinase domain mutations upon acquired resistance. N550 molecular brake and V565 gatekeeper mutations were most common, representing 63% and 47% of all FGFR2 kinase domain mutations, respectively. Functional studies showed different inhibitors displayed unique activity profiles against FGFR2 mutations. Interestingly, disruption of the cysteine residue covalently bound by futibatinib (FGFR2 C492) was rare, observed in 1 of 42 patients treated with this drug. FGFR2 C492 mutations were insensitive to inhibition by futibatinib but showed reduced signaling activity, potentially explaining their low frequency. CONCLUSIONS These data support secondary FGFR2 kinase domain mutations as the primary mode of acquired resistance to FGFR inhibitors, most commonly N550 and V565 mutations. Thus, development of combination strategies and next-generation FGFR inhibitors targeting the full spectrum of FGFR2 resistance mutations will be critical.
Collapse
Affiliation(s)
- Qibiao Wu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
- The Cancer Program, Broad Institute, Cambridge, Massachusetts
| | - Haley Ellis
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
- The Cancer Program, Broad Institute, Cambridge, Massachusetts
| | - Giulia Siravegna
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Alexa G. Michel
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Bryanna L. Norden
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Ferran Fece de la Cruz
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Eranga Roshan Balasooriya
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
- The Cancer Program, Broad Institute, Cambridge, Massachusetts
| | - Yuanli Zhen
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
- The Cancer Program, Broad Institute, Cambridge, Massachusetts
| | - Vanessa S. Silveira
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
- The Cancer Program, Broad Institute, Cambridge, Massachusetts
| | - Jianwe Che
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ryan B. Corcoran
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Nabeel Bardeesy
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
- The Cancer Program, Broad Institute, Cambridge, Massachusetts
| |
Collapse
|
44
|
Jara MA. Management of Advanced Medullary Thyroid Carcinoma: Current Systemic Therapy Options. Crit Rev Oncog 2024; 29:83-90. [PMID: 38683155 DOI: 10.1615/critrevoncog.2024051588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
The current rapid development of more selective and effective drugs for the treatment of thyroid cancer has open a new era in the treatment of patients with this condition, in the past limited to the possibility of only radioactive iodine for well differentiated tumor and surgery for medullary thyroid carcinoma (MTC). The treatment of advanced medullary thyroid carcinoma has evolved in the last few years and options for patients with advanced disease are now available. Multikinase inhibitors (MKIs) with nonselective RET inhibition like Vandetanib and Cabozantinib were approved for the treatment of MTC, although the efficacy is limited due to the lack of specificity resulting in a higher rate of drug-related adverse events, leading to subsequent dose reductions, or discontinuation, and the development of a resistance mechanism like seen on the RET Val804 gatekeeper mutations. MTC is associated with mutations in the RET protooncogene, and new highly selective RET inhibitors have been developed including Selpercatinib and Pralsetinib, drugs that have demonstrate excellent results in clinical trials, and efficacy even in the presence of gatekeeper mutations. However, despite their efficacy and great tolerability, mechanisms of resistance have been described, such as the RET solvent front mutations. Due to this, the need of constant evolution and drug research is necessary to overcome the emergence of resistance mechanisms.
Collapse
|
45
|
Peng Y, Zheng Z, Zewen W, Yanan L, Mingyan Z, Meili S. Whole-exome sequencing explored mechanism of selpercatinib resistance in RET-rearranged lung adenocarcinoma transformation into small-cell lung cancer: a case report. BMC Pulm Med 2023; 23:492. [PMID: 38057798 PMCID: PMC10698965 DOI: 10.1186/s12890-023-02799-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023] Open
Abstract
Small cell transformation was one mechanism by which EGFR-mutation NSCLC acquired resistance after tyrosine kinase inhibitors (TKIs) treatment. A few reports of small cell transformation occurred in other oncogene-driven lung cancers. We found the first case of transformation of a RET-rearranged lung adenocarcinoma to SCLC after selpercatinib, a novel highly selective RET TKIs. Whole-exome sequencing (WES) was used to explore alteration in gene expression in tumor tissue at initial diagnosis and after transformation into small cell carcinoma. We found that transformed into SCLC tumor tissue had inactivation of RB1 and TP53, with RET fusion was still present. In addition, the APOBEC family of cytidine deaminases appeared amplification. Although RET rearrangement still existed, using another RET TKIs was ineffective, and etoposide plus platinum might be an effective rescue treatment.
Collapse
Affiliation(s)
- Yan Peng
- Oncology Department, Central Hospital Affiliated to Shandong First Medical University, Jinan, P. R. China
| | - Zhu Zheng
- Research Department, PLA Rocket Force Characteristic Medical Center, Beijing, P.R. China
| | - Wang Zewen
- Oncology Department, Central Hospital Affiliated to Shandong First Medical University, Jinan, P. R. China
| | - Liu Yanan
- Oncology Department, Central Hospital Affiliated to Shandong First Medical University, Jinan, P. R. China
| | - Zhang Mingyan
- School of Medicine, Shandong University, Jinan, P. R. China
| | - Sun Meili
- Oncology Department, Central Hospital Affiliated to Shandong First Medical University, Jinan, P. R. China.
| |
Collapse
|
46
|
Vakkalagadda CV, Patel JD. Addition of Trastuzumab Deruxtecan to Selpercatinib in a Patient With RET Fusion-Driven NSCLC and an Acquired HER2 Amplification: Case Report. JTO Clin Res Rep 2023; 4:100603. [PMID: 38144396 PMCID: PMC10746506 DOI: 10.1016/j.jtocrr.2023.100603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2023] Open
Abstract
Despite the high activity of selective RET inhibitors in RET-driven NSCLC, resistance eventually develops and there is unmet need to better define therapeutic options for patients. This is a case of a patient initially thought to have no targetable alterations, then found to have a RET fusion, and subsequently HER2 amplification on three distinct biopsies. She was treated initially with chemotherapy and immune therapy, then switched to selpercatinib, and eventually had fam-trastuzumab deruxtecan added to selpercatinib. She also developed neuroendocrine differentiation at time of progression in the context of a p53 mutation, which is a known factor that can lead to small cell transformation. This patient's case highlights the need for comprehensive molecular testing at both diagnosis and progression, as unexpected resistance mechanisms may be identified particularly for patients with uncommon driver mutations.
Collapse
Affiliation(s)
- Chetan V. Vakkalagadda
- Department of Medicine, Division of Hematology and Oncology, Northwestern University, Chicago, Illinois
- Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
| | - Jyoti D. Patel
- Department of Medicine, Division of Hematology and Oncology, Northwestern University, Chicago, Illinois
| |
Collapse
|
47
|
[Chinese Expert Consensus on the Clinical Practice of Non-small Cell Lung Cancer
Fusion Gene Detection Based on RNA-based NGS]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2023; 26:801-812. [PMID: 37985137 PMCID: PMC10714047 DOI: 10.3779/j.issn.1009-3419.2023.102.43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Indexed: 11/22/2023]
Abstract
RNA-based next-generation sequencing (NGS) has been recommended as a method for detecting fusion genes in non-small cell lung cancer (NSCLC) according to clinical practice guidelines and expert consensus. The primary targetable alterations in NSCLC consist of gene mutations and fusions, making the detection of gene mutations and fusions indispensable for assessing the feasibility of targeted therapies. Currently, the integration of DNA-based NGS and RNA-based NGS allows for simultaneous detection of gene mutations and fusions and has been partially implemented in clinical practice. However, standardized guidelines and criteria for the significance, application scenarios, and quality control of RNA-based NGS in fusion gene detection are still lacking in China. This consensus aims to provide further clarity on the practical significance, application scenarios, and quality control measures of RNA-based NGS in fusion gene detection. Additionally, it offers guiding recommendations to facilitate the clinical implementation of RNA-based NGS in the diagnosis and treatment of NSCLC, ultimately maximizing the benefits for patients from fusion gene detection.
.
Collapse
|
48
|
Pu X, Xu C, Wang Q, Wang W, Wu F, Cai X, Song Z, Yu J, Zhong W, Wang Z, Zhang Y, Liu J, Zhang S, Liu A, Li W, Zhan P, Liu H, Lv T, Miao L, Min L, Lin G, Huang L, Yuan J, Jiang Z, Rao C, Lv D, Yu Z, Li X, Tang C, Zhou C, Zhang J, Guo H, Chu Q, Meng R, Liu X, Wu J, Zhou J, Zhu Z, Pan W, Pang F, Huang J, Wang K, Wu F, Shen T, Zou S, Xu B, Wang L, Zhu Y, Lin X, Cai J, Xu L, Li J, Jiao X, Li K, Feng H, Wang L, Du Y, Yao W, Shi X, Niu X, Yuan D, Yao Y, Kang J, Zhang J, Zhang C, Fu J, Huang J, Zhang Y, Sun P, Wang H, Ye M, Wang D, Wang Z, Hao Y, Wang Z, Wan B, Lv D, Lan G, Yang S, Shi L, Wang Y, Li B, Zhang Z, Li Z, Li Y, Liu Z, Yang N, Wang H, Huang W, Hong Z, Wang G, Wang J, Fang M, Fang Y, Zhu X, Shen Y, Zhang Y, Ma S, Song Y, Lu Y, et alPu X, Xu C, Wang Q, Wang W, Wu F, Cai X, Song Z, Yu J, Zhong W, Wang Z, Zhang Y, Liu J, Zhang S, Liu A, Li W, Zhan P, Liu H, Lv T, Miao L, Min L, Lin G, Huang L, Yuan J, Jiang Z, Rao C, Lv D, Yu Z, Li X, Tang C, Zhou C, Zhang J, Guo H, Chu Q, Meng R, Liu X, Wu J, Zhou J, Zhu Z, Pan W, Pang F, Huang J, Wang K, Wu F, Shen T, Zou S, Xu B, Wang L, Zhu Y, Lin X, Cai J, Xu L, Li J, Jiao X, Li K, Feng H, Wang L, Du Y, Yao W, Shi X, Niu X, Yuan D, Yao Y, Kang J, Zhang J, Zhang C, Fu J, Huang J, Zhang Y, Sun P, Wang H, Ye M, Wang D, Wang Z, Hao Y, Wang Z, Wan B, Lv D, Lan G, Yang S, Shi L, Wang Y, Li B, Zhang Z, Li Z, Li Y, Liu Z, Yang N, Wang H, Huang W, Hong Z, Wang G, Wang J, Fang M, Fang Y, Zhu X, Shen Y, Zhang Y, Ma S, Song Y, Lu Y, Fang W, Li Z, Wu L. Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China. Thorac Cancer 2023; 14:3166-3177. [PMID: 37718634 PMCID: PMC10626248 DOI: 10.1111/1759-7714.15105] [Show More Authors] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 08/29/2023] [Indexed: 09/19/2023] Open
Abstract
The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.
Collapse
Affiliation(s)
- Xingxiang Pu
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityCentral South UniversityChangshaPeople's Republic of China
| | - Chunwei Xu
- Institute of Cancer and Basic Medicine (ICBM)Chinese Academy of SciencesHangzhouPeople's Republic of China
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Qian Wang
- Department of Respiratory MedicineAffiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese MedicineNanjingPeople's Republic of China
| | - Wenxian Wang
- Department of ChemotherapyChinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital)HangzhouPeople's Republic of China
| | - Fang Wu
- Department of Oncology, The Second Xiangya HospitalCentral South UniversityChangshaPeople's Republic of China
| | - Xiuyu Cai
- Department of VIP Inpatient, Sun Yat‐Sen University Cancer Center, State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
| | - Zhengbo Song
- Department of ChemotherapyChinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital)HangzhouPeople's Republic of China
| | - Jinpu Yu
- Department of Cancer Molecular Diagnostics CoreTianjin Medical University Cancer Institute and HospitalTianjinPeople's Republic of China
| | - Wenzhao Zhong
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical Sciences, School of MedicineGuangzhouPeople's Republic of China
| | - Zhijie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Yongchang Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaPeople's Republic of China
| | - Jingjing Liu
- Department of Thoracic CancerJilin Cancer HospitalJilinPeople's Republic of China
| | - Shirong Zhang
- Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer CenterZhejiang University School of MedicineHangzhouPeople's Republic of China
| | - Anwen Liu
- Department of OncologySecond Affiliated Hospital of Nanchang UniversityNanchangPeople's Republic of China
| | - Wen Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Cancer CenterZhejiang UniversityHangzhouPeople's Republic of China
| | - Ping Zhan
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Hongbing Liu
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Tangfeng Lv
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Liyun Miao
- Department of Respiratory Medicine, Affiliated Drum Tower HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Lingfeng Min
- Department of Respiratory MedicineClinical Medical School of Yangzhou University, Subei People's Hospital of Jiangsu ProvinceYangzhouPeople's Republic of China
| | - Gen Lin
- Department of Medical OncologyFujian Medical University Cancer Hospital & Fujian Cancer HospitalFuzhouPeople's Republic of China
| | - Long Huang
- Department of OncologySecond Affiliated Hospital of Nanchang UniversityNanchangPeople's Republic of China
| | - Jingping Yuan
- Department of PathologyRenmin Hospital of Wuhan UniversityWuhanPeople's Republic of China
| | - Zhansheng Jiang
- Department of Integrative OncologyTianjin Medical University Cancer Institute and HospitalTianjinPeople's Republic of China
| | - Chuangzhou Rao
- Department of Radiotherapy and Chemotherapy, Hwamei HospitalUniversity of Chinese Academy of SciencesNingboPeople's Republic of China
| | - Dongqing Lv
- Department of Pulmonary MedicineTaizhou Hospital of Wenzhou Medical UniversityTaizhouPeople's Republic of China
| | - Zongyang Yu
- Department of Respiratory Medicine, the 900th Hospital of the Joint Logistics Team (the Former Fuzhou General Hospital)Fujian Medical UniversityFuzhouPeople's Republic of China
| | - Xiaoyan Li
- Department of Oncology, Beijing Tiantan HospitalCapital Medical UniversityBeijingPeople's Republic of China
| | - Chuanhao Tang
- Department of Medical OncologyPeking University International HospitalBeijingPeople's Republic of China
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease; Guangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical University (The First Affiliated Hospital of Guangzhou Medical University)GuangzhouPeople's Republic of China
| | - Junping Zhang
- Department of Thoracic Oncology, Shanxi Academy of Medical SciencesShanxi Bethune HospitalTaiyuanPeople's Republic of China
| | - Hui Guo
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
| | - Rui Meng
- Cancer Center, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
| | - Xuewen Liu
- Department of Oncology, the Third Xiangya HospitalCentral South UniversityChangshaPeople's Republic of China
| | - Jingxun Wu
- Department of Medical Oncology, the First Affiliated Hospital of MedicineXiamen UniversityXiamenPeople's Republic of China
| | - Jin Zhou
- Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of MedicineUniversity of Electronic Science and TechnologyChengduPeople's Republic of China
| | - Zhengfei Zhu
- Department of Radiation OncologyFudan University Shanghai Cancer CenterShanghaiPeople's Republic of China
| | - Weiwei Pan
- Department of Cell Biology, College of MedicineJiaxing UniversityJiaxingPeople's Republic of China
| | - Fei Pang
- Department of MedicalShanghai OrigiMed Co, LtdShanghaiPeople's Republic of China
| | - Jintao Huang
- Department of MedicalShanghai OrigiMed Co, LtdShanghaiPeople's Republic of China
| | - Kai Wang
- Department of MedicalShanghai OrigiMed Co, LtdShanghaiPeople's Republic of China
| | - Fan Wu
- Department of MedicalMenarini Silicon Biosystems SpaShanghaiPeople's Republic of China
| | - Tingting Shen
- Department of MedicalStone Pharmaceuticals (Suzhou) Co., Ltd.ShanghaiPeople's Republic of China
| | - Shirui Zou
- Department of MedicalStone Pharmaceuticals (Suzhou) Co., Ltd.ShanghaiPeople's Republic of China
| | - Bingwei Xu
- Department of Biotherapy, Cancer InstituteFirst Affiliated Hospital of China Medical UniversityShenyangPeople's Republic of China
| | - Liping Wang
- Department of OncologyBaotou Cancer HospitalBaotouPeople's Republic of China
| | - Youcai Zhu
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun HospitalThe Third Affiliated Hospital of Jiaxing UniversityJiaxingPeople's Republic of China
| | - Xinqing Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease; Guangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical University (The First Affiliated Hospital of Guangzhou Medical University)GuangzhouPeople's Republic of China
| | - Jing Cai
- Department of OncologySecond Affiliated Hospital of Nanchang UniversityNanchangPeople's Republic of China
| | - Ling Xu
- Department of Interventional Pulmonary DiseasesAnhui Chest HospitalHefeiPeople's Republic of China
| | - Jisheng Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinnanPeople's Republic of China
| | - Xiaodong Jiao
- Department of Medical Oncology, Shanghai Changzheng HospitalNaval Medical UniversityShanghaiPeople's Republic of China
| | - Kainan Li
- Department of Oncology, Shandong Provincial Third Hospital, Cheeloo College of MedicineShandong UniversityJinanPeople's Republic of China
| | - Huijing Feng
- Department of Thoracic Oncology, Shanxi Academy of Medical SciencesShanxi Bethune HospitalTaiyuanPeople's Republic of China
| | - Lin Wang
- Department of Pathology, Shanxi Academy of Medical SciencesShanxi Bethune HospitalTaiyuanPeople's Republic of China
| | - Yingying Du
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China
| | - Wang Yao
- Department of Interventional Oncology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouPeople's Republic of China
| | - Xuefei Shi
- Department of Respiratory Medicine, Huzhou HospitalZhejiang University School of MedicineHuzhouPeople's Republic of China
| | - Xiaomin Niu
- Department of Shanghai Lung Cancer Center, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
| | - Dongmei Yuan
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Yanwen Yao
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Jing Kang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical Sciences, School of MedicineGuangzhouPeople's Republic of China
| | - Jiatao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical Sciences, School of MedicineGuangzhouPeople's Republic of China
| | - Chao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's HospitalGuangdong Academy of Medical Sciences, School of MedicineGuangzhouPeople's Republic of China
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua HospitalZhejiang University School of MedicineJinhuaPeople's Republic of China
| | - Jianhui Huang
- Department of OncologyLishui Municipal Central HospitalLishuiPeople's Republic of China
| | - Yinbin Zhang
- Department of Oncology, the Second Affiliated Hospital of Medical CollegeXi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Pingli Sun
- Department of PathologyThe Second Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Hong Wang
- Senior Department of OncologyThe 5th Medical Center of PLA General HospitalBeijingPeople's Republic of China
| | - Mingxiang Ye
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Dong Wang
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Zhaofeng Wang
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Yue Hao
- Department of ChemotherapyChinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital)HangzhouPeople's Republic of China
| | - Zhen Wang
- Department of Radiation Oncology, Affiliated Jinling HospitalMedical School of NanjingNanjingPeople's Republic of China
| | - Bing Wan
- Department of Respiratory MedicineThe Affiliated Jiangning Hospital of Nanjing Medical UniversityNanjingPeople's Republic of China
| | - Donglai Lv
- Department of Clinical OncologyThe 901 Hospital of Joint Logistics Support Force of People Liberation ArmyHefeiPeople's Republic of China
| | - Gang Lan
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun HospitalThe Third Affiliated Hospital of Jiaxing UniversityJiaxingPeople's Republic of China
| | - Shengjie Yang
- Department of Thoracic SurgeryChuxiong Yi Autonomous Prefecture People's HospitalChuxiongPeople's Republic of China
| | - Lin Shi
- Department of Respiratory Medicine, Zhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
| | - Yina Wang
- Department of Oncology, The First Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouPeople's Republic of China
| | - Bihui Li
- Department of OncologyThe Second Affiliated Hospital of Guilin Medical UniversityGuilinPeople's Republic of China
| | - Zhang Zhang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of PharmacyJinan UniversityGuangzhouPeople's Republic of China
| | - Zhongwu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of PathologyPeking University Cancer Hospital & InstituteBeijingPeople's Republic of China
| | - Yuan Li
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiPeople's Republic of China
| | - Zhefeng Liu
- Senior Department of OncologyThe 5th Medical Center of PLA General HospitalBeijingPeople's Republic of China
| | - Nong Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaPeople's Republic of China
| | - Huijuan Wang
- Department of Medical OncologyThe Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouPeople's Republic of China
| | - Wenbin Huang
- Department of Pathologythe First Affiliated Hospital of Henan University of Science and TechnologyLuoyangPeople's Republic of China
| | - Zhuan Hong
- Department of Medical Oncology, Jiangsu Cancer HospitalNanjing Medical University Affiliated Cancer HospitalNanjingPeople's Republic of China
| | - Guansong Wang
- Institute of Respiratory Diseases, Xinqiao HospitalThird Military Medical UniversityChongqingPeople's Republic of China
| | - Jiandong Wang
- Department of Pathology, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Meiyu Fang
- Department of ChemotherapyChinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital)HangzhouPeople's Republic of China
| | - Yong Fang
- Department of Medical Oncology, Sir Run Run Shaw HospitalZhejiang UniversityHangzhouPeople's Republic of China
| | - Xixu Zhu
- Department of Radiation Oncology, Affiliated Jinling HospitalMedical School of NanjingNanjingPeople's Republic of China
| | - Yi Shen
- Department of Thoracic Surgery, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Yiping Zhang
- Department of ChemotherapyChinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital)HangzhouPeople's Republic of China
| | - Shenglin Ma
- Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Cancer CenterZhejiang University School of MedicineHangzhouPeople's Republic of China
| | - Yong Song
- Department of Respiratory Medicine, Affiliated Jinling HospitalMedical School of Nanjing UniversityNanjingPeople's Republic of China
| | - Yuanzhi Lu
- Department of Clinical PathologyThe First Affiliated Hospital of Jinan UniversityGuangzhouPeople's Republic of China
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
| | - Ziming Li
- Department of Shanghai Lung Cancer Center, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
| | - Lin Wu
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityCentral South UniversityChangshaPeople's Republic of China
| |
Collapse
|
49
|
Gild ML, Clifton-Bligh RJ, Wirth LJ, Robinson BG. Medullary Thyroid Cancer: Updates and Challenges. Endocr Rev 2023; 44:934-946. [PMID: 37204852 PMCID: PMC10656709 DOI: 10.1210/endrev/bnad013] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 03/19/2023] [Accepted: 05/18/2023] [Indexed: 05/20/2023]
Abstract
A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve.
Collapse
Affiliation(s)
- Matti L Gild
- Faculty of Health and Medicine, University of Sydney, Sydney 2006, Australia
- Department of Diabetes and Endocrinology, Royal North Shore Hospital, Sydney 2065, Australia
- Cancer Genetics, Kolling Institute of Medical Research, Sydney 2065, Australia
| | - Roderick J Clifton-Bligh
- Faculty of Health and Medicine, University of Sydney, Sydney 2006, Australia
- Department of Diabetes and Endocrinology, Royal North Shore Hospital, Sydney 2065, Australia
- Cancer Genetics, Kolling Institute of Medical Research, Sydney 2065, Australia
| | - Lori J Wirth
- Department of Medicine, Massachusetts General Hospital, & Harvard Medical School, Boston 02114, USA
| | - Bruce G Robinson
- Faculty of Health and Medicine, University of Sydney, Sydney 2006, Australia
- Department of Diabetes and Endocrinology, Royal North Shore Hospital, Sydney 2065, Australia
- Cancer Genetics, Kolling Institute of Medical Research, Sydney 2065, Australia
| |
Collapse
|
50
|
Kumaki Y, Oda G, Ikeda S. Targeting MET Amplification: Opportunities and Obstacles in Therapeutic Approaches. Cancers (Basel) 2023; 15:4552. [PMID: 37760522 PMCID: PMC10526812 DOI: 10.3390/cancers15184552] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/01/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification.
Collapse
Affiliation(s)
- Yuichi Kumaki
- Department of Specialized Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
| | - Goshi Oda
- Department of Specialized Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
| | - Sadakatsu Ikeda
- Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
- Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA
| |
Collapse
|