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Dera AA, Al Fayi M. CEG-0598, a novel dual inhibitor of EGFR and C5aR demonstrates in vitro anticancer and antimetastatic activity in prostate cancer cells. Discov Oncol 2025; 16:710. [PMID: 40343625 PMCID: PMC12064535 DOI: 10.1007/s12672-025-02574-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND The EGFR is abundantly expressed in prostate cancer (PC). The anaphylatoxin C5a induces leukocyte migration via the C5a receptor (C5aR) by releasing matrix metalloproteinases (MMP) to favor metastasis in the tumor microenvironment. This work aims to selectively inhibit the EGFR and C5aR in PC cells to abort cell growth/ proliferation and metastasis. METHODS For lead identification, high-throughput virtual screening (HTVS) of the ChemBridge library was followed by protein-ligand interaction profilers, GROMACS, and GMX-MMPBSA techniques. LNCaP and PC3 cells were used to validate in vitro efficacy. RESULTS HTVS identified CEG-0598 with favorable binding affinities of - 10.2 kcal/mol and - 13.5 kcal/mol towards EGFR and C5aR respectively. Molecular dynamic simulations demonstrated stable binding interactions for CEG-0598 with Root Mean Square Deviation values around 0.06 nm. The ΔG binding calculation was - 50.29, and - 51.64 for EGFR and C5aR respectively. ADME supported favorable small molecule characteristics and selective inhibition profiles. Kinome-wide off-target virtual screening predicted EGFR to have above-average docking scores. CEG-0598 inhibited EGFR and C5aR activities with IC50 values of 145.8 nM and 55.51 nM respectively. The compound effectively controlled the proliferation of LNCaP and PC3cells with GI50 values of 156.1 nM, and 112.2 nM respectively. CEG-0598 prompted dose-responsive apoptosis in the PC cells and decreased the tarns endothelial migration of both PC cells. Treatment with CEG-0598 reduced the C5a-induced MMP activity in the LNCaP and PC3cells. CONCLUSION CEG-0598 is a selective EGFR/C5a dual inhibitor that downregulates MMP activity to control proliferation, migration and induce apoptosis, in PC cells warranting further preclinical developments.
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Affiliation(s)
- Ayed A Dera
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
| | - Majed Al Fayi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
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Jang S, Jun H, Eom S, Zhao S, Murthy N, Kang S, Kim H. EGFR Affibody and PEG functionalized protein nanoparticles: Sustaining targeting and macrophage evasion. Int J Biol Macromol 2025; 307:142167. [PMID: 40118404 DOI: 10.1016/j.ijbiomac.2025.142167] [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: 11/07/2024] [Revised: 03/10/2025] [Accepted: 03/14/2025] [Indexed: 03/23/2025]
Abstract
When nanoparticles are introduced into a biological environment, serum proteins rapidly attach to their surfaces, leading to opsonization and subsequent rapid clearance by the immune system. In this study, we functionalized protein nanoparticles with PEG to impart stealth properties, aiming to reduce immune recognition. By incorporating EGFRAfb, we conferred targeting capabilities to the PEGylated protein nanoparticles, demonstrating their ability to specifically bind to target cells even after PEGylation. Additionally, the stealth effect conferred by PEGylation effectively prevented phagocytosis by macrophages. Taken together, these results indicate that PEGylated protein nanoparticles not only exhibit increased in vivo half-life due to reduced opsonization but also maintain cell-specific targeting capabilities.
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Affiliation(s)
- Seonhye Jang
- Department of Pharmaceutical Engineering, INJE University, Gimhae 50834, Republic of Korea
| | - Heejin Jun
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Soomin Eom
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Sheng Zhao
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA
| | - Niren Murthy
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA.
| | - Sebyung Kang
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
| | - Hansol Kim
- Department of Pharmaceutical Engineering, INJE University, Gimhae 50834, Republic of Korea.
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MODI SHAILRAKESH, ANDEY TERRICK. Piperlongumine in combination with EGFR tyrosine kinase inhibitors for the treatment of lung cancer cells. Oncol Res 2024; 32:1709-1721. [PMID: 39449797 PMCID: PMC11497197 DOI: 10.32604/or.2024.053972] [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: 05/15/2024] [Accepted: 08/09/2024] [Indexed: 10/26/2024] Open
Abstract
Objectives EGFR tyrosine kinase inhibitor (EGFR-TKI) therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer (NSCLC). However, the high incidence of acquired resistance to these EGFR-TKIs may preclude their effectiveness. Piperlongumine (PPL), an extract from the long pepper fruit (Piper longum), has been shown to possess anticancer properties. The purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer cells. Methods Anticancer efficacy of PPL, erlotinib (ERL), gefitinib (GEF), and cisplatin (CIS) were investigated in H1299 and H1975 cell lines. Cells were treated with PPL, ERL, GEF, and CIS alone, and in combination, cell viability was determined after 72 h. The mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species (ROS) induction, and apoptosis induction using acridine orange/ethidium bromide staining and flow cytometry. The effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic markers. Results PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL, GEF, and CIS. Combination treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines, which were associated with apoptotic induction, but without significant ROS induction. Compared to control, PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow cytometry. Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level. Conclusion PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.
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Affiliation(s)
- SHAIL RAKESH MODI
- Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, MA 01608, USA
| | - TERRICK ANDEY
- Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, MA 01608, USA
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Azad TD, Nanjo S, Jin MC, Chabon JJ, Kurtz DM, Chaudhuri AA, Connolly ID, Hui ABY, Liu CL, Merriott D, Ko R, Yoo C, Carter J, Chen E, Bonilla R, Hata A, Katakami N, Irie K, Yano S, Okimoto R, Bivona TG, Newman AM, Iv M, Nagpal S, Gephart MH, Alizadeh AA, Diehn M. Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis. NPJ Precis Oncol 2024; 8:121. [PMID: 38806586 PMCID: PMC11133465 DOI: 10.1038/s41698-024-00582-1] [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: 07/03/2023] [Accepted: 03/28/2024] [Indexed: 05/30/2024] Open
Abstract
Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.
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Affiliation(s)
- Tej D Azad
- Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| | - Shigeki Nanjo
- Department of Medicine, University of California, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
- Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Michael C Jin
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Jacob J Chabon
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| | - David M Kurtz
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Aadel A Chaudhuri
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA
| | - Ian D Connolly
- Department of Neurosurgery, Stanford University, Stanford, CA, USA
| | - Angela Bik-Yu Hui
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Chih Long Liu
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - David Merriott
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Ryan Ko
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Christopher Yoo
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Justin Carter
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Emily Chen
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Rene Bonilla
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Akito Hata
- Department of Medical Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Japan
| | - Nobuyuki Katakami
- Department of Medical Oncology, Takarazuka City Hospital, Hyogo, Japan
| | - Kei Irie
- Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, Kobe, Japan
| | - Seiji Yano
- Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Ross Okimoto
- Department of Medicine, University of California, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Trever G Bivona
- Department of Medicine, University of California, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Aaron M Newman
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Michael Iv
- Department of Radiology, Stanford University, Stanford, CA, USA
| | - Seema Nagpal
- Department of Neurology, Stanford University, Stanford, CA, USA
| | | | - Ash A Alizadeh
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
| | - Maximilian Diehn
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA.
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Hussain S, Mursal M, Verma G, Hasan SM, Khan MF. Targeting oncogenic kinases: Insights on FDA approved tyrosine kinase inhibitors. Eur J Pharmacol 2024; 970:176484. [PMID: 38467235 DOI: 10.1016/j.ejphar.2024.176484] [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: 09/24/2023] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 03/13/2024]
Abstract
Protein kinases play pivotal roles in various biological functions, influencing cell differentiation, promoting survival, and regulating the cell cycle. The disruption of protein kinase activity is intricately linked to pathways in tumor development. This manuscript explores the transformative impact of protein kinase inhibitors on cancer therapy, particularly their efficacy in cases driven by targeted mutations. Focusing on key tyrosine kinase inhibitors (TKIs) like Bcr-Abl, Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR), it targets critical kinase families in cancer progression. Clinical trial details of these TKIs offer insights into their therapeutic potentials. Learning from FDA-approved kinase inhibitors, the review dissects trends in kinase drug development since imatinib's paradigm-shifting approval in 2001. TKIs have evolved into pivotal drugs, extending beyond oncology. Ongoing clinical trials explore novel kinase targets, revealing the vast potential within the human kinome. The manuscript provides a detailed analysis of advancements until 2022, discussing the roles of specific oncogenic protein kinases in cancer development and carcinogenesis. Our exploration on PubMed for relevant and significant TKIs undergoing pre-FDA approval phase III clinical trials enriches the discussion with valuable findings. While kinase inhibitors exhibit lower toxicity than traditional chemotherapy in cancer treatment, challenges like resistance and side effects emphasize the necessity of understanding resistance mechanisms, prompting the development of novel inhibitors like osimertinib targeting specific mutant proteins. The review advocates thorough research on effective combination therapies, highlighting the future development of more selective RTKIs to optimize patient-specific cancer treatment and reduce adverse events.
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Affiliation(s)
- Sahil Hussain
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, 226026, India
| | - Mohd Mursal
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, 226026, India
| | - Garima Verma
- RWE Specialist, HealthPlix Technologies, Bengaluru, Karnataka 560103, India
| | - Syed Misbahul Hasan
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, 226026, India
| | - Mohemmed Faraz Khan
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, 226026, India.
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Yeh CY, Cai HY, Kuo HH, Lin YY, He ZJ, Cheng HC, Yang CJ, Huang CYF, Chang YC. ALDOA coordinates PDE3A through the β-catenin/ID3 axis to stimulate cancer metastasis and M2 polarization in lung cancer with EGFR mutations. Biochem Biophys Res Commun 2024; 696:149489. [PMID: 38244313 DOI: 10.1016/j.bbrc.2024.149489] [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: 10/30/2023] [Revised: 12/21/2023] [Accepted: 01/05/2024] [Indexed: 01/22/2024]
Abstract
Lung cancer has a high incidence rate and requires more effective treatment strategies and drug options for clinical patients. EGFR is a common genetic alteration event in lung cancer that affects patient survival and drug strategy. Our study discovered aberrant aldolase A (ALDOA) expression and dysfunction in lung cancer patients with EGFR mutations. In addition to investigating relevant metabolic processes like glucose uptake, lactate production, and ATPase activity, we examined multi-omics profiles (transcriptomics, proteomics, and pull-down assays). It was observed that phosphodiesterase 3A (PDE3A) enzyme and ALDOA exhibit correlation, and furthermore, they impact M2 macrophage polarization through β-catenin and downstream ID3. In addition to demonstrating the aforementioned mechanism of action, our experiments discovered that the PDE3 inhibitor trequinsin has a substantial impact on lung cancer cell lines with EGFR mutants. The trequinsin medication was found to decrease the M2 macrophage polarization status and several cancer phenotypes, in addition to transduction. These findings have potential prognostic and therapeutic applications for clinical patients with EGFR mutation and lung cancer.
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Affiliation(s)
- Chia-Ying Yeh
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Huei Yu Cai
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Han-His Kuo
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - You-Yu Lin
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Zhao-Jing He
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiao-Chen Cheng
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Jen Yang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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Tanabe KK, Zahrieh D, Strand CA, Hoshida Y, Flotte TJ, Della’Zanna G, Umar A, Chavin KD, Cleary S, Kubota N, Llovet JM, Patel T, Siegel C, Limburg PJ. Epidermal Growth Factor Receptor Inhibition With Erlotinib in Liver: Dose De-Escalation Pilot Trial as an Initial Step in a Chemoprevention Strategy. GASTRO HEP ADVANCES 2024; 3:426-439. [PMID: 39131140 PMCID: PMC11307768 DOI: 10.1016/j.gastha.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 01/19/2024] [Indexed: 08/13/2024]
Abstract
Background and Aims Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration-approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. Methods Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. Results A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib. Conclusion These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.govNCT02273362).
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Affiliation(s)
- Kenneth K. Tanabe
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - David Zahrieh
- Division of Clinical Trial and Biostatistics, Mayo Clinic, Rochester, New York
| | - Carrie A. Strand
- Division of Clinical Trial and Biostatistics, Mayo Clinic, Rochester, New York
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Thomas J. Flotte
- Mayo Clinic Pathology Research Core, Mayo Clinic, Rochester, New York
| | - Gary Della’Zanna
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Asad Umar
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Kenneth D. Chavin
- Department of Surgery, UH Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Sean Cleary
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, New York
| | - Naoto Kubota
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Josep M. Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Liver Unit, Translational Research in Hepatic Oncology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Tushar Patel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | | | - Paul J. Limburg
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, New York
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Saleh MM, El-Moselhy T, El-Bastawissy E, Ibrahim MAA, Sayed SRM, Hegazy MEF, Efferth T, Jaragh-Alhadad LA, Sidhom PA. The mystery of titan hunter: Rationalized striking of the MAPK pathway via Newly synthesized 6-Indolylpyridone-3-Carbonitrile derivatives. Eur J Med Chem 2023; 259:115675. [PMID: 37506545 DOI: 10.1016/j.ejmech.2023.115675] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/11/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
MAPK pathway sparkles with RTK activation, passes through subsequent downstream RAS-RAF-MEK-ERK signaling cascades, with consequent direct and indirect CDK4/6 signaling activation, and ends with cell survival, division, and proliferation. However, the emergence of anomalies such as mutations or overexpression in one or more points of the pathway could lead to cancer development and drug resistance. Therefore, designing small inhibitors to strike multitudinous MAPK pathway steps could be a promising synergistic strategy to confine cancer. In this study, twelve 6-indolylpyridone-3-carbonitrile candidates were synthesized and assessed in vitro for antineoplastic activity using four cancer cell lines. The initial antiproliferative screening revealed that compounds 3g, 3h, and 3i were the most potent candidates (GI% Avg = 70.10, 73.94, 74.33%, respectively) compared to staurosporine (GI% Avg = 70.99%). The subsequent safety and selectivity assessment showed that 3h exhibited sub-micromolar inhibition against lung cancer cells (HOP-92 GI50 = 0.75 μM) and 13.7 times selectivity toward cancerous cells over normal cells. As a result, 3h was nominated for deep mechanistic studies which evidenced that compound 3h impressively blocks multiple keystones of the MAPK pathway with nanomolar potency (EGFRWT IC50 = 281 nM, c-MET IC50 = 205 nM, B-RAFWT IC50 = 112 nM, and CDK4/6 IC50 = 95 and 184 nM, respectively). Surprisingly, 3h showed a remarkable potency against mutated EGFR and B-RAF, being 4 and 1.3 more selective to the mutated enzymes over the wild-type forms (EGFRT790M IC50 = 69 nM and B-RAFV600E IC50 = 83 nM). Ultimately, combined molecular docking and molecular dynamics (MD) calculations were executed to inspect the mode of binding and the complex stability of 3h towards the keystones of the MAPK pathway.
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Affiliation(s)
- Mohamed M Saleh
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, 31527, Tanta, Egypt.
| | - Tarek El-Moselhy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, 31527, Tanta, Egypt
| | - Eman El-Bastawissy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, 31527, Tanta, Egypt
| | - Mahmoud A A Ibrahim
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt; School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4000, South Africa
| | - Shaban R M Sayed
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Mohamed-Elamir F Hegazy
- Chemistry of Medicinal Plants Department, National Research Center, 33 El-Bohouth St., Dokki, Giza, 12622, Egypt; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany
| | | | - Peter A Sidhom
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, 31527, Tanta, Egypt.
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Sentana-Lledo D, Academia E, Viray H, Rangachari D, Kobayashi SS, VanderLaan PA, Costa DB. EGFR exon 20 insertion mutations and ERBB2 mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates. Transl Lung Cancer Res 2023; 12:1590-1610. [PMID: 37577308 PMCID: PMC10413034 DOI: 10.21037/tlcr-23-98] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 06/14/2023] [Indexed: 08/15/2023]
Abstract
Background and Objective This review will provide an overview of EGFR and ERBB2 mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals. Methods We obtained data from the literature in accordance with narrative review reporting guidelines. Key Content and Findings EGFR mutations are present in up to 15-20% of all NSCLCs; amongst these, 10% correspond to kinase domain insertions in exon 20. Structurally similar, ERBB2 (HER2) mutations occurs in 1-4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of EGFR exon 20 insertions occur within the loop following the regulatory C-helix and activate the kinase domain of EGFR without generating a therapeutic window to gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Mobocertinib represents a novel class of covalent EGFR inhibitors with a modest therapeutic window to these mutants and induces anti-tumor responses in a portion of patients [at 160 mg/day: response rate of <30% with duration of response (DoR) >17 months and progression-free survival (PFS) of >7 months] albeit with mucocutaneous and gastrointestinal toxicities. The bi-specific EGFR-MET antibody amivantamab-vmjw has modest but broad preclinical activity in EGFR-driven cancers and specifically for EGFR exon 20 insertion-mutated NSCLC has response rates <40% and PFS of <8.5 months at the cost of both infusion-related plus on-target toxicities. Both drugs were approved in 2021. The clinical development of kinase inhibitors for ERBB2-mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib. However, the activation of ERBB2 has allowed for repurposing of antibody-drug conjugates (ADCs) that target ERBB2 with cytotoxic payloads. The FDA approved fam-trastuzumab deruxtecan-nxki in 2022 for NSCLC based on response rate of >55%, DoR >9 months, PFS >8 months and manageable adverse events (including cytopenias, nausea and less commonly pneumonitis). Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors. Conclusions The approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for EGFR exon 20 insertion-mutated and ERBB2-mutated NSCLCs.
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Affiliation(s)
- Daniel Sentana-Lledo
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Emmeline Academia
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Hollis Viray
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Deepa Rangachari
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Susumu S. Kobayashi
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Paul A. VanderLaan
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Daniel B. Costa
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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10
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Nie L, Wang YN, Hsu JM, Hou J, Chu YY, Chan LC, Huo L, Wei Y, Deng R, Tang J, Hsu YH, Ko HW, Lim SO, Huang K, Chen MK, Chiu TJ, Cheng CC, Fang YF, Li CW, Goverdhan A, Wu HJ, Lee CC, Wang WL, Hsu J, Chiao P, Wang SC, Hung MC. Nuclear export signal mutation of epidermal growth factor receptor enhances malignant phenotypes of cancer cells. Am J Cancer Res 2023; 13:1209-1239. [PMID: 37168336 PMCID: PMC10164793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 02/16/2023] [Indexed: 05/13/2023] Open
Abstract
Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) in the EGFR NES led to increased nuclear accumulation of the protein via a less efficient release of the exportin CRM1. Interestingly, L747 with serine (L747S) and with proline (L747P) mutations were found in both tyrosine kinase inhibitor (TKI)-treated and -naïve patients with lung cancer who had acquired or de novo TKI resistance and a poor outcome. Reconstituted expression of the single NES mutant EGFRL747P or EGFRL747S, but not the dual mutant along with the internalization-defective or NLS mutation, in lung cancer cells promoted malignant phenotypes, including cell migration, invasiveness, TKI resistance, and tumor initiation, supporting an oncogenic role of nuclear EGFR. Intriguingly, cells with germline expression of the NES L747 mutant developed into B cell lymphoma. Mechanistically, nuclear EGFR signaling is required for sustaining nuclear activated STAT3, but not for Erk. These findings suggest that EGFR functions are compartmentalized and that nuclear EGFR signaling plays a crucial role in tumor malignant phenotypes, leading to tumorigenesis in human cancer.
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Affiliation(s)
- Lei Nie
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Ying-Nai Wang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Jung-Mao Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- Center for Molecular Medicine, China Medical University HospitalTaichung, Taiwan
| | - Junwei Hou
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Yu-Yi Chu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Li-Chuan Chan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Longfei Huo
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Yongkun Wei
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Rong Deng
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen UniversityGuangzhou, Guangdong, China
| | - Jun Tang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- Department of Breast Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou, Guangdong, China
| | - Yi-Hsin Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - How-Wen Ko
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of MedicineTaoyuan, Taiwan
| | - Seung-Oe Lim
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Kebin Huang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy, Guangxi Normal UniversityGuilin, Guangxi, China
| | - Mei-Kuang Chen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Tai-Jan Chiu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Chien-Chia Cheng
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Yueh-Fu Fang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of MedicineTaoyuan, Taiwan
| | - Chia-Wei Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Aarthi Goverdhan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Hsing-Ju Wu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- Department of Medical Research, Chang Bing Show Chwan Memorial HospitalChanghua, Taiwan
| | - Cheng-Chung Lee
- Center for Molecular Medicine, China Medical University HospitalTaichung, Taiwan
| | - Wen-Ling Wang
- Center for Molecular Medicine, China Medical University HospitalTaichung, Taiwan
| | - Jennifer Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Paul Chiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
| | - Shao-Chun Wang
- Center for Molecular Medicine, China Medical University HospitalTaichung, Taiwan
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas, USA
- Center for Molecular Medicine, China Medical University HospitalTaichung, Taiwan
- Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, China Medical UniversityTaichung, Taiwan
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11
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Lee SH, Jang HJ. Deep learning-based prediction of molecular cancer biomarkers from tissue slides: A new tool for precision oncology. Clin Mol Hepatol 2022; 28:754-772. [PMID: 35443570 PMCID: PMC9597228 DOI: 10.3350/cmh.2021.0394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/17/2022] [Indexed: 02/06/2023] Open
Abstract
Molecular tests are necessary to stratify cancer patients for targeted therapy. However, high cost and technical barriers limit the application of these tests, hindering optimal treatment. Recently, deep learning (DL) has been applied to predict molecular test results from digitized images of tissue slides. Furthermore, treatment response and prognosis can be predicted from tissue slides using DL. In this review, we summarized DL-based studies regarding the prediction of genetic mutation, microsatellite instability, tumor mutational burden, molecular subtypes, gene expression, treatment response, and prognosis directly from hematoxylin- and eosin-stained tissue slides. Although performance needs to be improved, these studies clearly demonstrated the feasibility of DL-based prediction of key molecular features in cancer tissues. With the accumulation of data and technical advances, the performance of the DL system could be improved in the near future. Therefore, we expect that DL could provide cost- and time-effective alternative tools for patient stratification in the era of precision oncology.
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Affiliation(s)
- Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyun-Jong Jang
- Catholic Big Data Integration Center, Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea,Corresponding author : Hyun-Jong Jang Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2-2258-7274, Fax: +82-2-532-9575, E-mail:
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12
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Lee JY, Yang H, Kim D, Kyaw KZ, Hu R, Fan Y, Lee SK. Antiproliferative Activity of a New Quinazolin-4(3H)-One Derivative via Targeting Aurora Kinase A in Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2022; 15:ph15060698. [PMID: 35745617 PMCID: PMC9228987 DOI: 10.3390/ph15060698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/31/2022] [Indexed: 02/04/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype. Although chemotherapy and targeted therapy are used for the treatment of patients with NSCLC, the survival rate remains very low. Recent findings suggested that aurora kinase A (AKA), a cell cycle regulator, is a potential target for NSCLC therapy. Previously, we reported that a chemical entity of quinazolin-4(3H)-one represents a new template for AKA inhibitors, with antiproliferative activity against cancer cells. A quinazolin-4(3H)-one derivative was further designed and synthesized in order to improve the pharmacokinetic properties and antiproliferation activity against NSCLC cell lines. The derivative, BIQO-19 (Ethyl 6-(4-oxo-3-(pyrimidin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl)imidazo [1,2-a]pyridine-2-carboxylate), exhibited improved solubility and antiproliferative activity in NSCLC cells, including epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI)-resistant NSCLC cells. BIQO-19 effectively inhibited the growth of the EGFR-TKI-resistant H1975 NSCLC cells, with the suppression of activated AKA (p-AKA) expression in these cells. The inhibition of AKA by BIQO-19 significantly induced G2/M phase arrest and subsequently evoked apoptosis in H1975 cells. In addition, the combination of gefitinib and BIQO-19 exhibited synergistic antiproliferative activity in NSCLC cells. These findings suggest the potential of BIQO-19 as a novel therapeutic agent for restoring the sensitivity of gefitinib in EGFR-TKI-resistant NSCLC cells.
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Affiliation(s)
- Ji Yun Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea; (J.Y.L.); (D.K.); (K.Z.K.); (R.H.)
| | - Huarong Yang
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550014, China;
| | - Donghwa Kim
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea; (J.Y.L.); (D.K.); (K.Z.K.); (R.H.)
| | - Kay Zin Kyaw
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea; (J.Y.L.); (D.K.); (K.Z.K.); (R.H.)
| | - Ruoci Hu
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea; (J.Y.L.); (D.K.); (K.Z.K.); (R.H.)
| | - Yanhua Fan
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550014, China;
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
- Correspondence: (Y.F.); (S.K.L.); Tel.: +82-2-880-2475 (S.K.L.)
| | - Sang Kook Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea; (J.Y.L.); (D.K.); (K.Z.K.); (R.H.)
- Correspondence: (Y.F.); (S.K.L.); Tel.: +82-2-880-2475 (S.K.L.)
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13
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Ali Z, Vildevall M, Rodriguez GV, Tandiono D, Vamvakaris I, Evangelou G, Lolas G, Syrigos KN, Villanueva A, Wick M, Omar S, Erkstam A, Schueler J, Fahlgren A, Jensen LD. Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer. J Exp Clin Cancer Res 2022; 41:58. [PMID: 35139880 PMCID: PMC8827197 DOI: 10.1186/s13046-022-02280-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 01/31/2022] [Indexed: 11/25/2022] Open
Abstract
Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days. Conclusions We conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02280-x.
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Affiliation(s)
| | | | | | | | | | - Georgios Evangelou
- 3rd Department of Internal Medicine and Laboratory, National & Kapodistrian University of Athens, Athens, Greece
| | - Georgios Lolas
- 3rd Department of Internal Medicine and Laboratory, National & Kapodistrian University of Athens, Athens, Greece.,InCELLiA P.C, Athens, Greece
| | - Konstantinos N Syrigos
- 3rd Department of Internal Medicine and Laboratory, National & Kapodistrian University of Athens, Athens, Greece
| | - Alberto Villanueva
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Oncobell Program, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.,Xenopat S.L., Parc Cientific de Barcelona (PCB), Barcelona, Spain
| | | | - Shenga Omar
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Campus US, Entrance 68, Pl. 08, SE-58185, Linköping, Sweden
| | | | | | - Anna Fahlgren
- BioReperia AB, Linköping, Sweden.,Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linöping, Sweden
| | - Lasse D Jensen
- BioReperia AB, Linköping, Sweden. .,Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Campus US, Entrance 68, Pl. 08, SE-58185, Linköping, Sweden.
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14
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MESSEHA SAMIAS, NEZAMI MOHAMMADA, HAGER STEVEN, SOLIMAN KARAMF. A Rare Presentation of a Non-Asian Female With Metastatic Non-small-cell Lung Cancer Harboring EGFR L747P Mutation With Clinical Response to Multi-targeted Epigenetic and EGFR Inhibition. Anticancer Res 2022; 42:441-447. [PMID: 34969754 PMCID: PMC9869492 DOI: 10.21873/anticanres.15502] [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: 09/29/2021] [Revised: 10/27/2021] [Accepted: 11/13/2021] [Indexed: 01/26/2023]
Abstract
BACKGROUND Activating mutations of the epidermal growth factor receptor (EGFR) gene have been utilized to predict the effectiveness of EGFR tyrosine kinase inhibitor (TKI) therapy. The most common EGFR mutations are exon 19 deletion and exon 21-point mutation, which are sensitive to EGFR TKI. However, rare/complex EGFR mutations still exist, data of which are scarce and controversial. Hence, their role in response to standard therapy remains uncertain. CASE REPORT We present the case of a patient diagnosed with stage IV lung adenocarcinoma for whom standard chemotherapies, including platinum agents, had failed. The patient was found to have an EGFR exon 19 (L747P) mutation, as evident in her liquid biopsy. This alteration has not been described before in the literature on non-Asian females. Data from the current case study highlight the aggressive nature of this type of EGFR mutation as indicated by the complete resistance to erlotinib. Using standard first-generation EGFR inhibitors in treating this point mutation was considered inadequate. However, this patient showed a substantial response when treated with erlotinib combined with epigenetic therapies, consisting of DNA methyltransferase and histone deacetylase inhibitors. For more than 8 years, the patient has been responding to combination therapy with a normal quality of life. CONCLUSION This case represents a possible novel approach to reducing resistance in patients harboring this rare EGFR mutation which may translate to better outcomes.
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Affiliation(s)
- SAMIA S. MESSEHA
- Division of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, U.S.A.
| | - MOHAMMAD A. NEZAMI
- Sahel Oncology, Orange Coast Medical Center of Hope, Newport Beach, CA, U.S.A
| | - STEVEN HAGER
- C CARE, California Cancer Associates for Research and Excellence, Fresno, CA, U.S.A
| | - KARAM F.A. SOLIMAN
- Division of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, U.S.A.
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15
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Jung HD, Sung YJ, Kim HU. Omics and Computational Modeling Approaches for the Effective Treatment of Drug-Resistant Cancer Cells. Front Genet 2021; 12:742902. [PMID: 34691155 PMCID: PMC8527086 DOI: 10.3389/fgene.2021.742902] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/20/2021] [Indexed: 02/05/2023] Open
Abstract
Chemotherapy is a mainstream cancer treatment, but has a constant challenge of drug resistance, which consequently leads to poor prognosis in cancer treatment. For better understanding and effective treatment of drug-resistant cancer cells, omics approaches have been widely conducted in various forms. A notable use of omics data beyond routine data mining is to use them for computational modeling that allows generating useful predictions, such as drug responses and prognostic biomarkers. In particular, an increasing volume of omics data has facilitated the development of machine learning models. In this mini review, we highlight recent studies on the use of multi-omics data for studying drug-resistant cancer cells. We put a particular focus on studies that use computational models to characterize drug-resistant cancer cells, and to predict biomarkers and/or drug responses. Computational models covered in this mini review include network-based models, machine learning models and genome-scale metabolic models. We also provide perspectives on future research opportunities for combating drug-resistant cancer cells.
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Affiliation(s)
- Hae Deok Jung
- Department of Chemical and Biomolecular Engineering (BK21 four), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Yoo Jin Sung
- Department of Chemical and Biomolecular Engineering (BK21 four), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Hyun Uk Kim
- Department of Chemical and Biomolecular Engineering (BK21 four), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.,KAIST Institute for Artificial Intelligence, KAIST, Daejeon, South Korea.,BioProcess Engineering Research Center and BioInformatics Research Center KAIST, Daejeon, South Korea
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16
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Koh SB, Ross K, Isakoff SJ, Melkonjan N, He L, Matissek KJ, Schultz A, Mayer EL, Traina TA, Carey LA, Rugo HS, Liu MC, Stearns V, Langenbucher A, Saladi SV, Ramaswamy S, Lawrence MS, Ellisen LW. RASAL2 Confers Collateral MEK/EGFR Dependency in Chemoresistant Triple-Negative Breast Cancer. Clin Cancer Res 2021; 27:4883-4897. [PMID: 34168046 DOI: 10.1158/1078-0432.ccr-21-0714] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/30/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens. EXPERIMENTAL DESIGN We performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors. RESULTS We reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo. In patients with TNBC, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic Yes-Associated Protein (YAP). Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing. CONCLUSIONS These findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.
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Affiliation(s)
- Siang-Boon Koh
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Kenneth Ross
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts
| | - Steven J Isakoff
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Nsan Melkonjan
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Lei He
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Karina J Matissek
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Andrew Schultz
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Erica L Mayer
- Harvard Medical School, Boston, Massachusetts.,Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Lisa A Carey
- University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Hope S Rugo
- University of California San Francisco, San Francisco, California
| | - Minetta C Liu
- Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia
| | - Vered Stearns
- Johns Hopkins University and Sidney Kimmel Cancer Center, Baltimore, Maryland
| | - Adam Langenbucher
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Srinivas Vinod Saladi
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Sridhar Ramaswamy
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts.,Ludwig Center at Harvard, Harvard University, Boston, Massachusetts
| | - Michael S Lawrence
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts
| | - Leif W Ellisen
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts. .,Harvard Medical School, Boston, Massachusetts.,Ludwig Center at Harvard, Harvard University, Boston, Massachusetts
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17
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EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC: From molecular mechanisms to clinical research. Pharmacol Res 2021; 167:105583. [PMID: 33775864 DOI: 10.1016/j.phrs.2021.105583] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 12/15/2022]
Abstract
With the development of precision medicine, molecular targeted therapy has been widely used in the field of cancer, especially in non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a well-recognized and effective target for NSCLC therapies, targeted EGFR therapy with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has achieved ideal clinical efficacy in recent years. Unfortunately, resistance to EGFR-TKIs inevitably occurs due to various mechanisms after a period of therapy. EGFR mutations, such as T790M and C797S, are the most common mechanism of EGFR-TKI resistance. Here, we discuss the mechanisms of EGFR-TKIs resistance induced by secondary EGFR mutations, highlight the development of targeted drugs to overcome EGFR mutation-mediated resistance, and predict the promising directions for development of novel candidates.
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18
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Liu W, Yuan R, Hou A, Tan S, Liu X, Tan P, Huang X, Wang J. Ganoderma triterpenoids attenuate tumour angiogenesis in lung cancer tumour-bearing nude mice. PHARMACEUTICAL BIOLOGY 2020; 58:1061-1068. [PMID: 33161828 PMCID: PMC7655057 DOI: 10.1080/13880209.2020.1839111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 09/28/2020] [Accepted: 10/14/2020] [Indexed: 06/11/2023]
Abstract
CONTEXT Ganoderma lucidum (Leyss. ex Fr.) Karst. (Polyporaceae) triterpenoids (GLTs), the main components and bioactive metabolites of G. lucidum, have antitumour activity. OBJECTIVE We investigated the effects of GLTs in lung cancer tumour-bearing nude mice and their potential mechanism. MATERIALS AND METHODS Forty BALB/c nude mice were randomly divided into four groups: saline control, GLT (1 g/kg/day), gefitinib (GEF, 15 mg/kg/day), and GLT (1 g/kg/day) + GEF (15 mg/kg/day) for 14 days. Cell viability was conducted using the Cell Counting Kit-8 assay. The tumour volume, inhibition rate, histopathological, microvessel density (MVD), mRNAs, and proteins were determined. RESULTS GLTs inhibited the cell viability of A549 cells with an IC50 value of 14.38 ± 0.29 mg/L, while the IC50 value of GEF was 10.26 ± 0.47 μmol/L. The tumour inhibition rate in the GLT + GEF group (51.54%) was significantly decreased relative to the saline control… group (p < 0.05). The MVD in the GLT + GEF group (2.9 ± 0.7) was significantly decreased than that in the saline control group (12.8 ± 1.4, p < 0.05). The angiostatin, endostatin, and Bax protein expression in the GLT, GEF, and GLT + GEF groups were significantly increased compared to those in the saline control group, while the VEGFR2 and Bcl-2 protein expression were decreased. DISCUSSION AND CONCLUSIONS Our study provided evidence that GLT and GEF combination therapy may be a promising candidate for the treatment of lung cancer and as an experimental basis for clinical treatment.
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Affiliation(s)
- Wei Liu
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | | | - Aihua Hou
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Song Tan
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Xin Liu
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Pengcheng Tan
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Xiaoming Huang
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Jinguo Wang
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
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19
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Chemotherapy should be performed in epidermal growth factor receptor mutation-positive lung adenocarcinoma patients who had progressive disease to the first epidermal growth factor receptor-tyrosine kinase inhibitor. Anticancer Drugs 2020; 31:959-965. [PMID: 32889898 DOI: 10.1097/cad.0000000000000917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
After the failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, some non-small cell lung cancer patients desire to receive switching with another EGFR-TKI (TKI-switching), although cytotoxic chemotherapy has been recommended as second-line therapy. It is unclear who should not receive TKI-switching in these patients. We retrospectively evaluated overall survival (OS) from the initiation of first EGFR-TKI (first-TKI) therapy in advanced lung adenocarcinoma patients with active EGFR mutations (deletion of exon 19 or L858R in exon 21) who received TKI-switching according to the best response of the first-TKI. There was no difference in the OS between patients receiving TKI-switching (n = 35) and patients receiving additional chemotherapy between the first-TKI and second-TKI therapy (n =10) (P = 0.614). Among patients receiving TKI-switching, the OS in cases with progressive disease to the first-TKI (n = 9) was shorter than that in cases with disease control to the first-TKI (n = 26) (12.7 months vs. 49.4 months, P < 0.001). Five of the nine progressive disease cases who received TKI-switching missed an opportunity to receive chemotherapy. Their OS tended to be shorter than that in patients who received chemotherapy during the whole period of anticancer therapy (12.2 months vs. 20.3 months, P = 0.060). The multivariate analysis showed that disease control to the first-TKI therapy (P = 0.005) or the presence of chemotherapy (P = 0.087) decreased the risk of mortality. Chemotherapy should be performed in patients with progressive disease to the first-TKI.
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20
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Mulshine JL, Ujhazy P, Antman M, Burgess CM, Kuzmin I, Bunn PA, Johnson BE, Roth JA, Pass HI, Ross SM, Aldige CR, Wistuba II, Minna JD. From clinical specimens to human cancer preclinical models-a journey the NCI-cell line database-25 years later. J Cell Biochem 2020; 121:3986-3999. [PMID: 31803961 PMCID: PMC7496084 DOI: 10.1002/jcb.29564] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 11/13/2019] [Indexed: 01/24/2023]
Abstract
The intramural the National Cancer Institute (NCI) and more recently the University of Texas Southwestern Medical Center with many different collaborators comprised a complex, multi-disciplinary team that collaborated to generated large, comprehensively annotated, cell-line related research resources which includes associated clinical, and molecular characterization data. This material has been shared in an anonymized fashion to accelerate progress in overcoming lung cancer, the leading cause of cancer death across the world. However, this cell line collection also includes a range of other cancers derived from patient-donated specimens that have been remarkably valuable for other types of cancer and disease research. A comprehensive analysis conducted by the NCI Center for Research Strategy of the 278 cell lines reported in the original Journal of Cellular Biochemistry Supplement, documents that these cell lines and related products have since been used in more than 14 000 grants, and 33 207 published scientific reports. This has resulted in over 1.2 million citations using at least one cell line. Many publications involve the use of more than one cell line, to understand the value of the resource collectively rather than individually; this method has resulted in 2.9 million citations. In addition, these cell lines have been linked to 422 clinical trials and cited by 4700 patents through publications. For lung cancer alone, the cell lines have been used in the research cited in the development of over 70 National Comprehensive Cancer Network clinical guidelines. Finally, it must be underscored again, that patient altruism enabled the availability of this invaluable research resource.
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Affiliation(s)
- James L. Mulshine
- Center for Healthy Aging, Department of Internal MedicineRush UniversityChicagoIllinois
| | - Peter Ujhazy
- Translational Research Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteRockvilleMaryland
| | - Melissa Antman
- Center for Research StrategyNational Cancer InstituteBethesdaMaryland
| | | | - Igor Kuzmin
- Translational Research Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteRockvilleMaryland
| | - Paul A. Bunn
- University of Colorado Cancer CenterUniversity of Colorado Cancer CenterAuroraColorado
| | - Bruce E. Johnson
- Department of Medical OncologyDana‐Farber Cancer InstituteBostonMassachusetts
| | - Jack A. Roth
- Department of Thoracic and Cardiovascular Surgery, Division of SurgeryThe University of Texas MD Anderson Cancer CenterHoustonTexas
| | - Harvey I. Pass
- Department of Cardiothoracic SurgeryNew York University Langone Medical CenterNew YorkNew York
| | - Sheila M. Ross
- AdvocacyLung Cancer AllianceAnnapolisMaryland,MemberIASLC Early Detection and Screening CommitteeAuroraColorado
| | | | - Ignacio I. Wistuba
- Department of Translational Molecular PathologyUT MD Anderson Cancer CenterHoustonTexas
| | - John D Minna
- Nancy B. and Jake L. Hamon Center for Therapeutic Oncology ResearchUT Southwestern Medical CenterDallasTexas
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21
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Shriyan B, Patil D, Gurjar M, Nookala M, Patil A, Kannan S, Patil V, Joshi A, Noronha V, Prabhash K, Gota V. Safety and CSF distribution of high-dose erlotinib and gefitinib in patients of non-small cell lung cancer (NSCLC) with brain metastases. Eur J Clin Pharmacol 2020; 76:1427-1436. [PMID: 32529316 DOI: 10.1007/s00228-020-02926-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 06/01/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Patients of non-small cell lung cancer (NSCLC) with brain metastases have limited treatment options. High-dose erlotinib (HDE) and gefitinib (HDG) have been tried in the past. This study investigates the cerebrospinal fluid (CSF) disposition and safety of both, high-dose erlotinib and gefitinib regimens. METHODS Eleven and nine patients were treated with erlotinib and gefitinib, respectively. All patients received 1 week of standard dose of erlotinib (150 mg OD) or gefitinib (250 mg OD), followed by the high dose (1500 mg weekly for erlotinib and 1250 mg OD for gefitinib) from day 8. Blood and CSF samples were collected on days 7 and 15, 4 h after the morning dose and drug levels determined using LC-MS/MS. Adverse events were documented as per CTCAE 4.03 till day 15. RESULTS Pulsatile HDE and daily HDG resulted in 1.4- and 1.9-fold increase in CSF levels, respectively. A constant 2% CSF penetration rate was observed across both doses of erlotinib, while for gefitinib the penetration rate for high dose was half that of the standard dose suggesting a nonlinear disposition. Three patients on HDE treatment discontinued treatment after the first dose due to intolerable toxicities, whereas HDG was better tolerated with no treatment discontinuations. Since CSF disposition of gefitinib followed saturable kinetics, a lower dose of 750 mg was found to achieve CSF concentrations comparable to that of the 1250 mg dose. CONCLUSIONS HDG was better tolerated than HDE. CSF disposition of gefitinib was found to be saturable at a higher dose. Based on these findings, the dose of 750 mg OD should be considered for further evaluation in this setting.
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Affiliation(s)
- Bharati Shriyan
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Deepali Patil
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Murari Gurjar
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Manjunath Nookala
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Anand Patil
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Sadhana Kannan
- Department of Biostatistics, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Vijay Patil
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, 400012, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, 400012, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, 400012, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, 400012, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Vikram Gota
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, 410210, India.
- Homi Bhabha National Institute, Mumbai, 400094, India.
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22
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Iwama E, Sakai K, Hidaka N, Inoue K, Fujii A, Nakagaki N, Ota K, Toyozawa R, Azuma K, Nakatomi K, Harada T, Hisasue J, Sakata S, Shimose T, Kishimoto J, Nakanishi Y, Nishio K, Okamoto I. Longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors. Cancer 2020; 126:219-227. [DOI: 10.1002/cncr.32481] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/30/2019] [Indexed: 08/30/2023]
Affiliation(s)
- Eiji Iwama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Kazuko Sakai
- Department of Genome Biology Kindai University Faculty of Medicine Osaka‐Sayama Japan
| | - Noriko Hidaka
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Koji Inoue
- Department of Respiratory Medicine Kitakyushu Municipal Medical Center Kita‐Kyushu Japan
| | - Akiko Fujii
- Department of Respiratory Medicine Koga Hospital 21 Kurume Japan
| | - Noriaki Nakagaki
- Department of Respiratory Medicine Steel Memorial Yawata Hospital Kita‐Kyushu Japan
| | - Keiichi Ota
- Department of Respiratory Medicine National Hospital Organization Fukuoka‐higashi Medical Center Fukuoka‐Koga Japan
| | - Ryo Toyozawa
- Department of Thoracic Oncology National Kyushu Cancer Center Fukuoka Japan
| | - Koichi Azuma
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine Kurume University School of Medicine Kurume Japan
| | - Keita Nakatomi
- Department of Respiratory Medicine Kyushu Chuo Hospital Fukuoka Japan
| | - Taishi Harada
- Department of Respiratory Medicine Japan Community Healthcare Organization Kyushu Hospital Kita‐Kyushu Japan
| | - Junko Hisasue
- Department of Respiratory Medicine Hara Sanshin Hospital Fukuoka Japan
| | - Shinya Sakata
- Department of Respiratory Medicine, Faculty of Life Sciences Kumamoto University Kumamoto Japan
| | | | - Junji Kishimoto
- Department of Research and Development of Next Generation Medicine Kyushu University Fukuoka Japan
| | - Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Kazuto Nishio
- Department of Genome Biology Kindai University Faculty of Medicine Osaka‐Sayama Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
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23
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Pharmacophore modeling, 3D-QSAR, docking and ADME prediction of quinazoline based EGFR inhibitors. ARAB J CHEM 2019. [DOI: 10.1016/j.arabjc.2016.09.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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24
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Fang YH, Yang YH, Hsieh MJ, Hung MS, Lin YC. Concurrent proton-pump inhibitors increase risk of death for lung cancer patients receiving 1st-line gefitinib treatment - a nationwide population-based study. Cancer Manag Res 2019; 11:8539-8546. [PMID: 31572008 PMCID: PMC6756852 DOI: 10.2147/cmar.s222278] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 08/31/2019] [Indexed: 12/12/2022] Open
Abstract
Purpose Concurrent proton pump inhibitor (PPI) use might reduce the plasma concentration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Clinically, the adverse effect of PPIs on patients with non-small cell lung cancer (NSCLC) treated with first-line EGFR TKIs remains controversial. This study was conducted to evaluate whether the combined use of gefitinib with PPIs affected NSCLC outcomes. Patients and methods We performed a nationwide cohort study of patients newly diagnosed with NSCLC between 1997 and 2013 using the Taiwan Cancer Registry and Taiwan National Health Insurance databases. We identified patients who were treated with first-line EGFR TKIs and analyzed the association between use of PPIs and TKI treatment outcome. We defined the coverage ratio of PPIs as duration of PPI treatment in days divided by duration of TKIs in days. Patients who exhibited an overlap of >20% between PPI and TKI usage days were defined as having a high coverage ratio. Results A total of 1278 patients were treated with first-line gefitinib, 309 of which took PPIs at the same time and 145 had a high PPI coverage ratio. Patients had similar time to failure regardless of their PPI coverage ratio during gefitinib treatment. However, higher PPI coverage ratio significantly decreased overall survival (OS) compared with that of patients with a lower PPI coverage ratio or no PPI treatment in univariate analysis (median OS, 13.5, 16.7, and 21.8 months, respectively, p<0.01) and multivariate analyses (high coverage ratio HR: 1.67; low coverage ratio HR: 1.29). Exposure to PPIs during first line gefitinib treatment significantly decreased overall survival of patients with NSCLC. Conclusion Concurrent use of PPIs was associated with lower overall survival in patients with EGFR-mutant NSCLC under first-line gefitinib treatment.
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Affiliation(s)
- Yu-Hung Fang
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C.,Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C.,Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei City, Taiwan, R.O.C.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.C
| | - Meng-Jer Hsieh
- Department of Respiratory Therapy, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.C.,Division of Pulmonary Infection and Critical Care Medicine, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C
| | - Ming-Szu Hung
- Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Puzi City, Chiayi County, Taiwan, R.O.C.,School of Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.C
| | - Yu-Ching Lin
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C.,Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Puzi City, Chiayi County, Taiwan, R.O.C
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25
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Kim M, Mun H, Sung CO, Cho EJ, Jeon HJ, Chun SM, Jung DJ, Shin TH, Jeong GS, Kim DK, Choi EK, Jeong SY, Taylor AM, Jain S, Meyerson M, Jang SJ. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat Commun 2019; 10:3991. [PMID: 31488816 PMCID: PMC6728380 DOI: 10.1038/s41467-019-11867-6] [Citation(s) in RCA: 487] [Impact Index Per Article: 81.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 08/06/2019] [Indexed: 12/16/2022] Open
Abstract
Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalised medicine. Here, we report lung cancer organoids and normal bronchial organoids established from patient tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2-mutant organoid to olaparib, an EGFR-mutant organoid to erlotinib, and an EGFR-mutant/MET-amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials.
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Affiliation(s)
- Minsuh Kim
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea
| | - Hyemin Mun
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea
| | - Chang Oak Sung
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eun Jeong Cho
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea
| | - Hye-Joon Jeon
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea
| | - Sung-Min Chun
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Da Jung Jung
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Seoul, South Korea
| | - Tae Hoon Shin
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Seoul, South Korea
| | - Gi Seok Jeong
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Seoul, South Korea
| | - Dong Kwan Kim
- Department of Thoracic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eun Kyung Choi
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seong-Yun Jeong
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Alison M Taylor
- Department of Medical Oncology and Center for Cancer-Genome Discovery, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Sejal Jain
- Department of Medical Oncology and Center for Cancer-Genome Discovery, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Matthew Meyerson
- Department of Medical Oncology and Center for Cancer-Genome Discovery, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Se Jin Jang
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea.
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
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26
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Makimoto G, Ohashi K, Senoo S, Hotta K, Maeda Y, Kiura K. Beneficial Effect of Osimertinib Readministration in Non-small-cell Lung Cancer Harboring an Epidermal Growth Factor Receptor (EGFR) Mutation with a History of Acquired Resistance to Osimertinib. Intern Med 2019; 58:1625-1627. [PMID: 30713295 PMCID: PMC6599916 DOI: 10.2169/internalmedicine.2152-18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
We herein report a case of the beneficial effect of osimertinib readministration in non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A 69-year-old non-smoking woman was diagnosed with advanced NSCLC harboring an EGFR exon19 deletion and T790M. She was treated with osimertinib for two years but eventually acquired resistance. After 1.5 years of salvage chemotherapies, osimertinib was re-administered. She has been effectively and safely treated with osimertinib readministration for over 10 months. A prospective study is warranted to evaluate the efficacy and safety of osimertinib readministration in NSCLC with EGFR mutations.
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Affiliation(s)
- Go Makimoto
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Kadoaki Ohashi
- Department of Respiratory Medicine, Okayama University Hospital, Japan
| | - Satoru Senoo
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Katsuyuki Hotta
- Center of Innovative Clinical Medicine, Okayama University Hospital, Japan
| | - Yoshinobu Maeda
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Katsuyuki Kiura
- Department of Respiratory Medicine, Okayama University Hospital, Japan
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27
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Wang X, Li W, Zhang N, Zheng X, Jing Z. Opportunities and challenges of co-targeting epidermal growth factor receptor and autophagy signaling in non-small cell lung cancer. Oncol Lett 2019; 18:499-506. [PMID: 31289521 DOI: 10.3892/ol.2019.10372] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 04/11/2019] [Indexed: 12/17/2022] Open
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a standard therapy for patients with non-small cell lung cancer (NSCLC) with sensitive mutations. However, acquired resistance emerges following a median of 6-12 months. Several studies demonstrated that EGFR-TKI-induced tumor microenvironment stresses and autophagy are important causes of resistance. The current review summarizes the molecular mechanisms involved in EGFR-mediated regulation of autophagy. The role of autophagy in EGFR-TKI treatment, which may serve a role in protection or cell death, was discussed. Furthermore, co-inhibiting EGFR and autophagy signaling as a rational therapeutic strategy in the treatment of patients with NSCLC was explored.
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Affiliation(s)
- Xiaoju Wang
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China
| | - Wenxin Li
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China
| | - Ni Zhang
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China
| | - Xiaoli Zheng
- Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China
| | - Zhao Jing
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China
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Liang SK, Ko JC, Yang JCH, Shih JY. Afatinib is effective in the treatment of lung adenocarcinoma with uncommon EGFR p.L747P and p.L747S mutations. Lung Cancer 2019; 133:103-109. [PMID: 31200815 DOI: 10.1016/j.lungcan.2019.05.019] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 05/13/2019] [Accepted: 05/16/2019] [Indexed: 12/28/2022]
Abstract
OBJECTIVES Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line standard treatment for advanced lung adenocarcinoma with mutant EGFR. Nevertheless, few studies have demonstrated the efficacy of first- and second-generation EGFR TKIs in patients harboring the uncommon p.L747P and p.L747S mutations in exon 19 of EGFR. MATERIALS AND METHODS From 2005-2018, we identified patients with lung adenocarcinoma with EGFR p.L747P or p.L747S mutations using DNA and cDNA sequencing or commercial kits and recorded their clinical data. Published data pertaining to these mutations were also reviewed. RESULTS Twelve eligible patients were enrolled at National Taiwan University Hospital (NTUH), and ten additional patients were identified in published literature. In NTUH cohort, the direct DNA sequencing had a 60.0% (3 of 5 patients) false-negative rate, and use of commercial kits all caused misidentification of EGFR p.L747P or p.L747S. Of the 7 patients receiving EGFR TKI treatment, five stage-IV lung adenocarcinoma patients that received afatinib had a 80.0% objective response rate (ORR), while two patients administered gefitinib or erlotinib showed a 0% ORR. The median progression-free survival (PFS) rates were 11.97 and 0.92 months (P = 0.012) for afatinib and gefitinib/erlotinib, respectively. No patients (0%) acquired p.T790 M resistance after failure of afatinib (n = 3). Of 10 patients harboring EGFR p.L747P from published literature, six patients used first-generation EGFR TKIs as treatment also showed 0% ORR and 1.00 month median PFS. CONCLUSIONS Patients with the uncommon EGFR mutations p.L747P and p.L747S could be incorrectly classified as having wild-type EGFR or a 19DEL when using direct DNA sequencing or commercial kits. Moreover, use of afatinib may provide significantly improved PFS in patients with advanced lung adenocarcinoma with one of these two EGFR mutations.
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Affiliation(s)
- Sheng-Kai Liang
- Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Jen-Chung Ko
- Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | | | - Jin-Yuan Shih
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
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Gu B, Wang J, Song Y, Wang Q, Wu Q. Retracted: The prognosis analysis of epidermal growth factor receptor tyrosine kinase inhibitor targeted treatment combined with chemotherapy in smokers with nonsmall cell lung cancer. J Cell Biochem 2019; 120:8798. [PMID: 30368879 DOI: 10.1002/jcb.27811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 09/12/2018] [Indexed: 02/02/2023]
Affiliation(s)
- Biao Gu
- Department of Thoracic Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Jipeng Wang
- Department of Respiratory Medicine, The Affiliated Huaian No.1 People´s Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Yaqi Song
- Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Qi Wang
- Department of Thoracic Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Qingquan Wu
- Department of Thoracic Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
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Yang L, Li J, Xu L, Lin S, Xiang Y, Dai X, Liang G, Huang X, Zhu J, Zhao C. Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway. Cancer Manag Res 2019; 11:1167-1176. [PMID: 30774444 PMCID: PMC6362962 DOI: 10.2147/cmar.s171517] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Non-small-cell lung cancer (NSCLC) comprises about 85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. The IL-6/STAT3 signaling pathway plays a pivotal role in NSCLC biology. Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that Rhein has significant antitumor effects, supporting the potential uses of Rhein as an antitumor agent. METHODS Cell viability and colony formation were performed to examine Rhein's potent anti-proliferative effect in human NSCLC cell lines PC-9, H460 and A549. Flow cytometry-based assay was employed to study whether Rhein could affect cell apoptosis and cycle. The expression level of P-STAT3, apoptosis and cycle-related proteins Bcl-2, Bax, MDM2, CDC2, P53 and CyclinB1 were detected by Western blotting. The xenograft models were used to evaluate the in vivo effect of Rhein. RESULTS We found that Rhein could significantly reduce the viability and stimulate apoptosis in human NSCLC cells in a dose-dependent manner. Western blot analysis results suggested that the antitumor effect of Rhein might be mediated via STAT3 inhibition. Rhein upregulated the expression of the proapoptotic protein Bax and downregulated the expression of the antiapoptotic protein Bcl-2. In addition, Rhein induced the arrest of NSCLC cells in the G2/M phase of the cell cycle and dose dependently inhibited the expression of cycle-related proteins. The Rhein also inhibited tumor growth in H460 xenograft models. CONCLUSION Rhein shows potent efficacy against NSCLC through inhibiting the STAT3 pathway. Our results also suggest that Rhein has a promising potential to be used as a novel antitumor agent for the treatment of NSCLC.
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Affiliation(s)
- Lehe Yang
- Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China, ,
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China,
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Jifa Li
- Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China, ,
| | - Lingyuan Xu
- Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China, ,
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China,
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Shichong Lin
- Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China, ,
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China,
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Youqun Xiang
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Xuanxuan Dai
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China,
| | - Xiaoying Huang
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Jiandong Zhu
- Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China, ,
| | - Chengguang Zhao
- Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China, ,
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China,
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31
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Value-added anticancer reactivity of sub-5 nm Ag-drug nanoparticles derived from organosilver(I) MOF. Sci China Chem 2018. [DOI: 10.1007/s11426-018-9376-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kim S, Park AK, Cho J. Early emergence of de novo EGFR T790M gatekeeper mutations during erlotinib treatment in PC9 non-small cell lung cancer cells. Biochem Biophys Res Commun 2018; 503:710-714. [PMID: 29909007 DOI: 10.1016/j.bbrc.2018.06.065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 06/13/2018] [Indexed: 10/28/2022]
Abstract
The emergence of the T790M gatekeeper mutation in the Epidermal Growth Factor Receptor (EGFR) gene is an important mechanism that can lead to the acquired resistance to EGFR-targeted tyrosine kinase inhibitors such as erlotinib or gefitinib. These drugs have been used in treating a subset of non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. Here we investigated the paths leading to the acquisition of the T790M mutation by establishing an erlotinib resistant PC9 cell model harboring ectopically introduced EGFR cDNA. We detected the emergence of T790M mutation within the EGFR cDNA in a subset of erlotinib resistant PC9 cell models through Sanger sequencing and droplet digital PCR-based methods, demonstrating that T790M mutation can emerge via de novo events following treatment with erlotinib. In addition, we show that the de novo T790M bearing erlotinib resistant PC9 cells are sensitive to the 3rd generation EGFR-targeted drug, WZ4002. Furthermore, GFP-based competition cell proliferation assays reveal that PC9 cells ectopically expressing EGFR mutant become more rapidly resistant to erlotinib than parental PC9 cells through the acquisition of the T790M mutation. Taken together, we believe that our findings expand upon the previous notion of evolutionary paths of T790M development, providing an important clue to designing a therapeutic strategy to overcome drug resistance.
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Affiliation(s)
- Sujin Kim
- Department of Nanobiomedical Science, Dankook University, Cheonan, 31116, Republic of Korea
| | - Angela Kj Park
- Department of Nanobiomedical Science, Dankook University, Cheonan, 31116, Republic of Korea
| | - Jeonghee Cho
- Department of Nanobiomedical Science, Dankook University, Cheonan, 31116, Republic of Korea.
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33
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Zhang XW, Liu W, Jiang HL, Mao B. Chinese Herbal Medicine for Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2018; 46:923-952. [PMID: 30001642 DOI: 10.1142/s0192415x18500490] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chinese herbal medicine (CHM) has been widely used in the treatment of advanced non-small-cell lung cancer (NSCLC), but their efficacy and safety remain controversial. We sought to comprehensively aggregate and evaluate the available evidence on the efficacy and safety of the combination treatment with CHM and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC patients. Our exhausted and systematical searching strategy yielded 64 related randomized controlled trials involving 4384 patients. Compared with EGFR-TKIs therapy alone, meta-analysis showed significant differences favoring the combination treatment in progression-free survival ([Formula: see text]), median survival time ([Formula: see text]), one-year survival rate ([Formula: see text]), two-year survival rate ([Formula: see text]), probability of severe toxicities ([Formula: see text]), objective response rate ([Formula: see text]), Karnofsky performance status ([Formula: see text]), and improvement in percentage of CD3[Formula: see text] T lymphocyte ([Formula: see text]) and CD4[Formula: see text] T lymphocyte ([Formula: see text]). Though these results require further confirmation, they are prone to show a potential therapeutic value of CHM in improving the clinical effect, overcoming the drug resistance and toxicities as an adjunctive therapy to EGFR-TKIs.
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Affiliation(s)
- Xia-Wei Zhang
- 1 Division of Respiratory Medicine, Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, P. R. China
| | - Wei Liu
- 1 Division of Respiratory Medicine, Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, P. R. China
| | - Hong-Li Jiang
- 1 Division of Respiratory Medicine, Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, P. R. China
| | - Bing Mao
- 1 Division of Respiratory Medicine, Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, P. R. China
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34
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The role of T790M mutation in EGFR-TKI re-challenge for patients with EGFR-mutant advanced lung adenocarcinoma. Oncotarget 2018; 8:4994-5002. [PMID: 27999211 PMCID: PMC5354886 DOI: 10.18632/oncotarget.14007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 12/05/2016] [Indexed: 11/25/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) T790M mutation has shown to be associated with the clinical outcomes of patients after initial EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy in EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, its predictive role in EGFR-TKI re-challenge remains unknown. The present study was aimed to explore the correlation between T790M mutation and any benefits from EGFR-TKI re-challenge. We retrospectively reviewed 922 consecutive patients with EGFR-mutant non-small cell lung cancer (NSCLC) patients administered with gefitinib/erlotinib at Guangdong General Hospital. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were analyzed respectively. In total, 66 EGFR-mutant patients with stage IV adenocarcinoma were eligible, of whom 51 underwent re-biopsy upon initial progression. Among them, 18 (35.3%) harbored T790M mutation. No statistical significant differences were seen between T790M-positive and T790M-negative patients in PFS, OS, ORR or DCR. The median PFS, median OS, ORR, and DCR of the overall 66 patients were 2.0 months, 6.8 months, 6.1% and 39.4%, respectively. Good performance status (PS) was found to be independent favorable prognostic factor and long TKI-free interval to be associated with superior PFS. In conclusion, T790M mutation might not predict the clinical outcomes in first-generation EGFR-TKI re-challenge. Based on the poor efficacy from our data, re-challenge of first-generation EGFR-TKIs could not be recommended routinely, but for those with good PS and long TKI-free interval, it might be an alternative option.
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35
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Pilotto S, Rossi A, Vavalà T, Follador A, Tiseo M, Galetta D, Morabito A, Di Maio M, Martelli O, Caffo O, Piovano PL, Cortinovis D, Zilembo N, Casartelli C, Banna GL, Ardizzoia A, Barzelloni ML, Bearz A, Genestreti G, Mucciarini C, Filipazzi V, Menis J, Rizzo E, Barbieri F, Rijavec E, Cecere F, Spitaleri G, Bria E, Novello S. Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study. Clin Lung Cancer 2018. [DOI: 10.1016/j.cllc.2017.05.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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36
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Mohamad N, Jayalakshmi P, Rhodes A, Liam CK, Tan JL, Yousoof S, Rajadurai P. Anaplastic lymphoma kinase (ALK) mutations in patients with adenocarcinoma of the lung. Br J Biomed Sci 2017; 74:176-180. [PMID: 28705139 DOI: 10.1080/09674845.2017.1331520] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death. Approximately 2-16% of NSCLC patients with wild-type epidermal growth factor receptor (EGFR) harbour anaplastic lymphoma kinase (ALK) mutations. Both EGFR and ALK mutations occur most commonly in Asian patients with NSCLC. As targeted therapy is available for NSCLC patients with these mutations, it is important to establish reliable assays and testing strategies to identify those most likely to benefit from this therapy. MATERIALS AND METHODS Patients diagnosed with adenocarcinoma of the lung between 2010 and 2014 were tested for EGFR mutations. Of these, 92 cases were identified as EGFR wild type and suitable candidates for ALK testing utilising immunohistochemistry and the rabbit monoclonal antibody D5F3. The reliability of the IHC was confirmed by validating the results against those achieved by fluorescence in situ hybridisation (FISH) to detect ALK gene rearrangements. RESULTS Twelve (13%) cases were positive for ALK expression using immunohistochemistry. Of the 18 evaluable cases tested by FISH, there was 100% agreement with respect to ALK rearrangement/ALK expression between the assays, with 11 cases ALK negative and 7 cases ALK positive by both assays. ALK tumour expression was significantly more common in female compared to male patients (29.6% vs. 6.2%, P < 0.001), detected exclusively in patients that had never smoked (P < 0.001) and more frequently in metastases (22.7%) than in primary tumours (10%) (P = 0.047). CONCLUSIONS Detection of ALK expression by IHC is reliable and the most practical way of identifying NSCLC patients likely to benefit from crizotinib treatment.
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Affiliation(s)
- N Mohamad
- a Department of Pathology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - P Jayalakshmi
- a Department of Pathology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - A Rhodes
- a Department of Pathology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - C-K Liam
- b Department of Medicine, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - J-L Tan
- b Department of Medicine, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - S Yousoof
- c Subang Jaya Medical Centre , Selangor , Malaysia
| | - P Rajadurai
- c Subang Jaya Medical Centre , Selangor , Malaysia
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Nakamura T, Watanabe N, Sato A, Komiya K, Umeguchi H, Hosomi T, Hirai M, Sueoka E, Kimura S, Sueoka-Aragane N. Plasma T790M and HGF as potential predictive markers for EGFR-TKI re-challenge. Oncol Lett 2017; 13:4939-4946. [PMID: 28588734 DOI: 10.3892/ol.2017.6085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 02/23/2017] [Indexed: 12/15/2022] Open
Abstract
Re-challenge with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has been suggested to potentially improve survival in certain populations of patients with advanced lung cancer, but predictive markers for the success of EGFR-TKI re-challenge have not been identified. The present study analyzed 16 re-challenges with EGFR-TKI undertaken in 12 patients with lung adenocarcinoma by investigating T790M and hepatocyte growth factor (HGF) in plasma coupled with clinical characteristics. EGFR mutations in plasma DNA were detected using the wild inhibiting PCR and quenched probe system for exon 19 deletions, and T790M and L858R were detected using the mutation-biased PCR and quenched probe system. HGF levels in the plasma were measured by enzyme-linked immunosorbent assay, and the ratio of HGF levels prior to re-challenge to those prior to the previous EGFR-TKI treatment was calculated. Two re-challenges demonstrated partial response, six remained as stable disease and eight had progressive disease (PD). A total of 4 of the 5 patients with a history of T790M positivity based on plasma DNA levels had PD. A total of 7 of the 8 patients who had ≥1.5-fold elevation of HGF prior to re-challenge with EGFR-TKI suffered PD. Elevation of the HGF ratio to ≥1.5 was significantly associated with poor response to EGFR-TKI re-challenge. Having no history of T790M and an HGF ratio <1.5 was significantly associated with a positive response to EGFR-TKI re-challenge. A combination of T790M detection and HGF quantification using plasma is a potentially useful assay system for predicting the effect of EGFR-TKI re-challenge. Future prospective studies are required to confirm the predictive validity of these markers.
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Affiliation(s)
- Tomomi Nakamura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Naomi Watanabe
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Akemi Sato
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kazutoshi Komiya
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Hitomi Umeguchi
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | | | | | - Eisaburo Sueoka
- Department of Laboratory Medicine, Saga University Hospital, Saga 849-8501, Japan
| | - Shinya Kimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Naoko Sueoka-Aragane
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
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Kwon BS, Park JH, Kim WS, Song JS, Choi CM, Rho JK, Lee JC. Predictive Factors for Switched EGFR-TKI Retreatment in Patients with EGFR-Mutant Non-Small Cell Lung Cancer. Tuberc Respir Dis (Seoul) 2017; 80:187-193. [PMID: 28416959 PMCID: PMC5392490 DOI: 10.4046/trd.2017.80.2.187] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 12/12/2016] [Accepted: 02/09/2017] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Third-generation tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKIs) have proved efficacious in treating non-small cell lung cancer (NSCLC) patients with acquired resistance resulting from the T790M mutation. However, since almost 50% patients with the acquired resistance do not harbor the T790M mutation, retreatment with first- or second-generation EGFR-TKIs may be a more viable therapeutic option. Here, we identified positive response predictors to retreatment, in patients who switched to a different EGFR-TKI, following initial treatment failure. METHODS This study retrospectively reviewed the medical records of 42 NSCLC patients with EGFR mutations, whose cancers had progressed following initial treatment with gefitinib or erlotinib, and who had switched to a different first-generation EGFR-TKI during subsequent retreatment. To identify high response rate predictors in the changed EGFR-TKI retreatment, we analyzed the relationship between clinical and demographic parameters, and positive clinical outcomes, following retreatment with EGFR-TKI. RESULTS Overall, 30 (71.4%) patients received gefitinib and 12 (28.6%) patients received erlotinib as their first EGFR-TKI treatment. Following retreatment with a different EGFR-TKI, the overall response and disease control rates were 21.4% and 64.3%, respectively. There was no significant association between their overall responses. The median progression-free survival (PFS) after retreatment was 2.0 months. However, PFS was significantly longer in patients whose time to progression was ≥10 months following initial EGFR-TKI treatment, who had a mutation of exon 19, or whose treatment interval was <90 days. CONCLUSION In patients with acquired resistance to initial EGFR-TKI therapy, switched EGFR-TKI retreatment may be a salvage therapy for individuals possessing positive retreatment response predictors.
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Affiliation(s)
- Byoung Soo Kwon
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Hyun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Woo Sung Kim
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joon Seon Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang-Min Choi
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Kyung Rho
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Cheol Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Berry W, Algar E, Kumar B, Desmond C, Swan M, Jenkins BJ, Croagh D. Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity in KRAS wild-type tumors. Int J Cancer 2017; 140:2331-2343. [PMID: 28198009 DOI: 10.1002/ijc.30648] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 01/11/2017] [Accepted: 02/07/2017] [Indexed: 01/06/2023]
Abstract
Pancreatic cancer (PC) is largely refractory to existing therapies used in unselected patient trials, thus emphasizing the pressing need for new approaches for patient selection in personalized medicine. KRAS mutations occur in 90% of PC patients and confer resistance to epidermal growth factor receptor (EGFR) inhibitors (e.g., panitumumab), suggesting that KRAS wild-type PC patients may benefit from targeted panitumumab therapy. Here, we use tumor tissue procured by endoscopic ultrasound-guided fine-needle aspirate (EUS-FNA) to compare the in vivo sensitivity in patient-derived xenografts (PDXs) of KRAS wild-type and mutant PC tumors to panitumumab, and to profile the molecular signature of these tumors in patients with metastatic or localized disease. Specifically, RNASeq of EUS-FNA-derived tumor RNA from localized (n = 20) and metastatic (n = 20) PC cases revealed a comparable transcriptome profile. Screening the KRAS mutation status of tumor genomic DNA obtained from EUS-FNAs stratified PC patients into either KRAS wild-type or mutant cohorts, and the engraftment of representative KRAS wild-type and mutant EUS-FNA tumor samples into NOD/SCID mice revealed that the growth of KRAS wild-type, but not mutant, PDXs was selectively suppressed with panitumumab. Furthermore, in silico transcriptome interrogation of The Cancer Genome Atlas (TCGA)-derived KRAS wild-type (n = 38) and mutant (n = 132) PC tumors revealed 391 differentially expressed genes. Taken together, our study validates EUS-FNA for the application of a novel translational pipeline comprising KRAS mutation screening and PDXs, applicable to all PC patients, to evaluate personalized anti-EGFR therapy in patients with KRAS wild-type tumors.
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Affiliation(s)
- William Berry
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia.,Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, 3168, Australia
| | - Elizabeth Algar
- Genetics and Molecular Pathology Laboratory, Monash Health, Clayton, VIC, 3168, Australia.,Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC, 3168, Australia
| | - Beena Kumar
- Department of Anatomical Pathology, Monash Health, Clayton, VIC, 3168, Australia
| | - Christopher Desmond
- Department of Gastroenterology, Monash Health, Clayton, VIC, 3168, Australia
| | - Michael Swan
- Department of Gastroenterology, Monash Health, Clayton, VIC, 3168, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia.,Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, 3168, Australia
| | - Daniel Croagh
- Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, 3800, Australia
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Cree IA, Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer 2017; 17:10. [PMID: 28056859 PMCID: PMC5214767 DOI: 10.1186/s12885-016-2999-1] [Citation(s) in RCA: 214] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 12/13/2016] [Indexed: 12/14/2022] Open
Abstract
Background The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Review Resistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients. Conclusion The oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.
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Affiliation(s)
- Ian A Cree
- Department of Pathology, University Hospitals Coventry and Warwickshire, Coventry, CV2 2DX, UK. .,Faculty of Health and Life Sciences, Coventry University, Priory Street, Coventry, CV1 5FB, UK.
| | - Peter Charlton
- Imperial Innovations, 52 Princes Gate, Exhibition Road, London, SW7 2PG, UK
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Recommendations of the Austrian Working Group on Pulmonary Pathology and Oncology for predictive molecular and immunohistochemical testing in non-small cell lung cancer. MEMO-MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2016. [DOI: 10.1007/s12254-016-0297-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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De Rosa V, Iommelli F, Monti M, Mainolfi CG, Fonti R, Del Vecchio S. Early 18F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors. EJNMMI Res 2016; 6:74. [PMID: 27726115 PMCID: PMC5056924 DOI: 10.1186/s13550-016-0229-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 10/04/2016] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. The aim of the present study was to test whether early changes of 18F-fluorodeoxyglucose (18F-FDG) uptake in animal models bearing erlotinib-resistant NSCLC may have different imaging patterns of response to erlotinib depending on the molecular mechanisms underlying resistance. Animal tumor models were developed using NSCLC H1975 cells bearing the T790M mutation and H1993 cells with MET amplification. Nude mice bearing erlotinib-resistant H1975 and H1993 xenografts (four animals for each cell line and for each treatment) were subjected to 18F-FDG PET/CT scan before and immediately after treatment (50 mg/kg p.o. for 3 days) with erlotinib, WZ4002, crizotinib, or vehicle. A three-dimensional region of interest analysis was performed to determine the percent change of 18F-FDG uptake in response to treatment. At the end of the imaging studies, tumors were removed and analyzed for glycolytic and mitochondrial proteins as well as levels of cyclin D1. RESULTS Imaging studies with 18F-FDG PET/CT in H1975 tumor-bearing mice showed a reduction of 18F-FDG uptake of 25.87 % ± 8.93 % after treatment with WZ4002 whereas an increase of 18F-FDG uptake up to 23.51 % ± 9.72 % was observed after treatment with erlotinib or vehicle. Conversely, H1993 tumors showed a reduction of 18F-FDG uptake after treatment with both crizotinib (14.70 % ± 1.30 %) and erlotinib (18.40 % ± 9.19 %) and an increase of tracer uptake in vehicle-treated (56.65 % ± 5.65 %) animals. The in vivo reduction of 18F-FDG uptake was always associated with downregulation of HKII and p-PKM2 Tyr105 glycolytic proteins and upregulation of mitochondrial complexes (subunits I-IV) in excised tumors. CONCLUSIONS 18F-FDG uptake is a reliable imaging biomarker of T790M-mediated resistance and its reversal in NSCLC whereas it may not be accurate in the detection of MET-mediated resistance.
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Affiliation(s)
- Viviana De Rosa
- Institute of Biostructures and Bioimaging, National Research Council, Via T. De Amicis 95, 80145, Naples, Italy
| | - Francesca Iommelli
- Institute of Biostructures and Bioimaging, National Research Council, Via T. De Amicis 95, 80145, Naples, Italy
| | - Marcello Monti
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, 80131, Naples, Italy
| | - Ciro Gabriele Mainolfi
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, 80131, Naples, Italy
| | - Rosa Fonti
- Institute of Biostructures and Bioimaging, National Research Council, Via T. De Amicis 95, 80145, Naples, Italy
| | - Silvana Del Vecchio
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, 80131, Naples, Italy.
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Pattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy. J Thorac Oncol 2016; 10:1601-7. [PMID: 26313684 DOI: 10.1097/jto.0000000000000648] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION The role of stereotactic body radiation therapy (SBRT) in patients with metastatic lung cancer harboring epidermal growth factor receptor (EGFR) mutations is not defined. We evaluated the pattern of failure in patients receiving tyrosine kinase inhibitor (TKI) therapy to identify candidates for consolidation SBRT. METHODS Computed tomography scans were reviewed in a cohort of EGFR-mutant patients enrolled on prospective TKI trials. Initial progression in sites of original disease (primary/metastatic) or new sites was classified as original site failure (OF) or distant site failure (DF), respectively. Simultaneous OF/DF was labeled ODF. Disease characteristics were analyzed for associations with patterns of failure using actuarial competing risks methodology. RESULTS Complete serial imaging was available in 49 patients with measurable disease. Median time to any progression was 8.3 months. The majority failed initially in original disease sites with OF, ODF, and DF frequencies being 47.0%, 32.6%, and 20.4%, respectively. Primary tumor size was the most significant predictor of OF in univariate and multivariate analysis (p = 0.004). Median time to progression was 3 months shorter in patients with OF compared with DF. Ten patients (20%) were retroactively classified as consolidation SBRT candidates based on the extent of disease at time of best response to TKI therapy, and in seven of these, initial progression occurred in original tumor sites. CONCLUSION Initial progression of TKI-treated cancers occurred predominantly in original disease sites. Consolidation SBRT was judged feasible in a subset of patients following maximum TKI response and may have prevented oligoprogression in most of these. In addition, we hypothesize that consolidation SBRT for residual disease could delay subsequent metastatic reseeding.
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Oda N, Ichihara E, Hotta K, Ninomiya K, Ninomiya T, Kubo T, Minami D, Murakami T, Yokoyama T, Harada D, Kuyama S, Ichikawa H, Inoue K, Kishino D, Inoue M, Takigawa N, Shibayama T, Harita S, Tanimoto M, Kiura K. Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403. Clin Lung Cancer 2016; 18:241-244. [PMID: 27506489 DOI: 10.1016/j.cllc.2016.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 07/05/2016] [Indexed: 11/19/2022]
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.
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Affiliation(s)
- Naohiro Oda
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Eiki Ichihara
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
| | - Katsuyuki Hotta
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan; Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Kiichiro Ninomiya
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Takashi Ninomiya
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Toshio Kubo
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Daisuke Minami
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan
| | - Toshi Murakami
- Department of Respiratory Medicine, Himeji Red Cross Hospital, Himeji, Japan
| | - Toshihide Yokoyama
- Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan
| | - Daijiro Harada
- Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Shoichi Kuyama
- Department of Respiratory Medicine, National Hospital Organization Iwakuni Medical Center, Yamaguchi, Japan
| | - Hirohisa Ichikawa
- Department of Respiratory Medicine, KKR Takamatsu Hospital, Takamatsu, Japan
| | - Koji Inoue
- Department of Respiratory Medicine, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Daizo Kishino
- Department of Respiratory Medicine, Himeji Red Cross Hospital, Himeji, Japan
| | - Masaaki Inoue
- Department of Thoracic Surgery, Shimonoseki City Hospital, Shimonoseki, Japan
| | - Nagio Takigawa
- Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Takuo Shibayama
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan
| | - Shingo Harita
- Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama, Japan
| | - Mitsune Tanimoto
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Katsuyuki Kiura
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
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Wang YT, Ning WW, Li J, Huang JA. Exon 19 L747P mutation presented as a primary resistance to EGFR-TKI: a case report. J Thorac Dis 2016; 8:E542-6. [PMID: 27499993 DOI: 10.21037/jtd.2016.05.95] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Active mutations of the EGFR gene have been proved to predict the activity of EGFR-TKI. The most common mutations are the exon 19 deletion and exon 21 point mutation, both of which are sensitive to EGFR-TKI. However, rare EGFR mutations or complex mutations still exist, and data of which are scarce and controversial. Their response to EGFR-TKI remains uncertain. We presented a patient diagnosed with stage IV lung adenocarcinoma who was found to have the EGFR mutation in exon 19 (L747P) before any treatment. The disease progressed 2 months after the chemotherapy containing cisplatin and pemetrexed, and erlotinib was administered, but there was no response found. This EGFR-TKI naïve patient failed to achieve the desired effect with the therapy of EGFR-TKI. L747P may be associated with primary resistance to EGFR-TKI in this case.
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Affiliation(s)
- Yu-Ting Wang
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wei-Wei Ning
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jing Li
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jian-An Huang
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
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Califano R, Romanidou O, Mountzios G, Landi L, Cappuzzo F, Blackhall F. Management of NSCLC Disease Progression After First-Line EGFR Tyrosine Kinase Inhibitors: What Are the Issues and Potential Therapies? Drugs 2016; 76:831-40. [PMID: 27129321 DOI: 10.1007/s40265-016-0578-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for advanced non-small cell lung cancer (NSCLC) patients whose tumor harbors an activating EGFR mutation. The vast majority of patients will experience disease control with an EGFR-TKI but inevitably all patients will progress, often within a year of treatment. There is no current standard of care for this scenario but, in clinical practice, most of the patients will be offered platinum-based doublet chemotherapy. In some situations, continuation of the EGFR-TKI beyond radiological progression, with or without use of local treatments in case of oligo-progressive disease, represents a reasonable therapeutic option. The aim of this review is to describe the different treatment strategies that have been developed to tackle progression on EGFR-TKIs, including specific clinical scenarios and novel agents designed to tackle the common T790M resistance mutation.
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Affiliation(s)
- Raffaele Califano
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK.
- Department of Medical Oncology, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
| | - Ourania Romanidou
- Medical Oncology Unit, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Giannis Mountzios
- Department of Medical Oncology, University of Athens School of Medicine, Athens, Greece
| | - Lorenza Landi
- Istituto Toscano Tumori, Ospedale Civile di Livorno,, Leghorn, Italy
| | - Federico Cappuzzo
- Istituto Toscano Tumori, Ospedale Civile di Livorno,, Leghorn, Italy
| | - Fiona Blackhall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK
- University of Manchester, Manchester, UK
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Yang CJ, Tsai MJ, Hung JY, Tsai YM, Lee JY, Chou SH, Liu TC, Shen MC, Huang MS, Chong IW. Poorer prognosis in Taiwanese female ever smokers with stage IV lung adenocarcinoma who were readministered a tyrosine kinase inhibitor. Onco Targets Ther 2016; 9:1511-8. [PMID: 27042119 PMCID: PMC4801161 DOI: 10.2147/ott.s100169] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Background Readministering a second epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with acquired resistance to an initial EGFR TKI is a common treatment strategy. However, the prognostic factors for the second EGFR TKI are still uncertain. Patients and methods In this retrospective study, we enrolled patients with stage IV lung adenocarcinoma diagnosed between June 2009 and October 2013 at two university-affiliated hospitals in Taiwan. Basic characteristics including age, sex, smoking status, performance status, EGFR mutation status, tumor response, and progression-free survival (PFS) of the second EGFR TKI (PFS2) were recorded. Results A total of 72 patients with stage IV adenocarcinoma with susceptible EGFR gene mutations who had been treated with a second EGFR TKI were enrolled. Survival analysis using the Kaplan–Meier method and log-rank test showed a significant difference in PFS2 when classifying the patients according to smoking history and sex (P=0.0179). When stratifying the patients by sex, a significant difference was found in PFS2 between ever smokers and never smokers in the female (1.87 vs 4.87 months, P=0.0081) but not in the male (2.83 vs 2.9 months, P=0.9605) patients. A reduced multivariate model developed using the backward variable selection method showed that only ever smoking remained an independent poor prognostic factor for PFS2, and that sex and ever smoking remained independent poor prognostic factors for PFS2 in the female patients (hazard ratio [HR] =3.386, 95% confidence interval [CI]: 1.015–11.298, P=0.0473). Conclusion This study is the first to demonstrate that female ever smokers have a poorer PFS if they have acquired resistance to an initial EGFR TKI and receive a second EGFR TKI. Further large-scale studies are urgently needed to elucidate the mechanism.
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Affiliation(s)
- Chih-Jen Yang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Ju Tsai
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jen-Yu Hung
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ying-Ming Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jui-Ying Lee
- Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shah-Hwa Chou
- Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ta-Chih Liu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mei-Chiou Shen
- Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Shyan Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Geriatric Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Inn-Wen Chong
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Miyazaki K, Sato S, Kodama T, Tamura T, Kagohashi K, Satoh H, Hizawa N. Effect of acid suppressants on the efficacy of tyrosine kinase inhibitors in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer. Mol Clin Oncol 2016; 4:873-877. [PMID: 27123299 DOI: 10.3892/mco.2016.810] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 02/22/2016] [Indexed: 11/06/2022] Open
Abstract
This retrospective study was conducted to evaluate whether oral acid suppressant (AS) therapy is associated with decreased efficacy of gefitinib and erlotinib, particularly in patients with mutated epidermal growth factor receptor (EGFR). A total of 46 consecutive patients with pathologically confirmed non-small-cell lung cancer (NSCLC), who were treated with tyrosine kinase inhibitors (TKIs) in two tertiary hospitals between September, 2005 and May, 2013, were retrospectively analyzed. Of the 46 patients, 11 received AS treatment. As regards age, gender, smoking history, performance status, histology of lung cancer, clinical stage, body surface area (BSA) and type of EGFR mutation, there were no statistically significant differences between patients with and those without AS treatment. There was no statistically significant difference in progression-free survival (PFS) or overall survival (OS) between the two groups of patients (P=0.296 and 0.613, respectively). As regards the relative dose of TKI/BSA and survival in patients with and those without AS treatment, there were no statistically significant differences in PFS and OS between the two groups of patients. Our study indicates that AS treatment may not compromise TKI efficacy (gefitinib or erlotinib) in NSCLC patients with mutated EGFR. Prospective studies and large-scale confirmation studies investigating the effect of AS co-administration with TKIs in patients with mutated EGFR may be meaningful in clinical practice.
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Affiliation(s)
- Kunihiko Miyazaki
- Ryugasaki Saiseikai General Hospital, Ryugasaki, Ibaraki 135-0033, Japan
| | - Shinya Sato
- Ryugasaki Saiseikai General Hospital, Ryugasaki, Ibaraki 135-0033, Japan
| | - Takahide Kodama
- Ryugasaki Saiseikai General Hospital, Ryugasaki, Ibaraki 135-0033, Japan
| | - Tomohiro Tamura
- Faculty of Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Katsunori Kagohashi
- Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba Hospital, University of Tsukuba, Mito, Ibaraki 310-0015, Japan
| | - Hiroaki Satoh
- Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba Hospital, University of Tsukuba, Mito, Ibaraki 310-0015, Japan
| | - Nobuyuki Hizawa
- Faculty of Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
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Lee VHF, Leung DKC, Choy TS, Lam KO, Lam PM, Leung TW, Kwong DLW. Efficacy and safety of afatinib in Chinese patients with EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) previously responsive to first-generation tyrosine-kinase inhibitors (TKI) and chemotherapy: comparison with historical cohort using erlotinib. BMC Cancer 2016; 16:147. [PMID: 26911310 PMCID: PMC4765101 DOI: 10.1186/s12885-016-2201-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 02/17/2016] [Indexed: 12/23/2022] Open
Abstract
Background Afaitnib has shown anti-tumor activity against metastatic EGFR-mutated NSCLC after prior failure to first generation EGFR-TKI and chemotherapy. We prospectively evaluated the efficacy and safety of afatinib in Chinese patients who previously failed first-generation TKI and chemotherapy under a compassionate use program (CUP) and compared to the erlotinib cohort. Methods Patients who suffered from metastatic EGFR-mutated NSCLC previously responsive to first-generation TKI and chemotherapy received afatinib until progression, loss of clinical benefits or intolerable toxicity. Treatment response, survival and safety were evaluated and compared to the erlotinib cohort. Results Twenty-five and 28 patients received afatinib and erlotinib respectively. More patients in the afatinib group had worse performance status (ECOG 2) than the erlotinib group (p = 0.008). After a median follow-up of 12.1 months, afatinib demonstrated comparable objective response rate (ORR) (20.0 % vs. 7.1 %, p = 0.17) but significantly higher disease control rate (DCR) (68.0 % vs. 39.3 %, p = 0.04) compared to erlotinib. Median progression-free survival (PFS) (4.1 months [95 % CI, 2.7–5.5 months] vs. 3.3 months [95 % CI, 2.2–4.3 months], p = 0.97) and overall survival (OS) were not different between the two groups (10.3 months [95 % CI, 7.5–13.0 months] vs. 10.8 months [95 % CI, 7.4–14.2 months], p = 0.51). Multivariate analyses revealed that age ≤70 years and time to progression (TTP) ≥18 months for the 1st TKI therapy were prognostic of PFS (p = 0.006 and p = 0.008 respectively). Afatinib caused less rash (60.0 % vs. 67.9 %, p = 0.04) but more diarrhea (60.0 % vs. 10.7 %, p = 0.002) compared to erlotinib. Conclusion Afatinib produced encouraging clinical efficacy as 2nd TKI therapy with manageable safety profiles in our Chinese patients after failure to another TKI and systemic chemotherapy. This study was registered at ClinicalTrials.gov (NCT02625168) on 3rd December 2015.
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Affiliation(s)
- Victor H F Lee
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 1/F, Professorial Block, 102 Pokfulam Road, Hong Kong, China.
| | - Dennis K C Leung
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 1/F, Professorial Block, 102 Pokfulam Road, Hong Kong, China.
| | - Tim-Shing Choy
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 1/F, Professorial Block, 102 Pokfulam Road, Hong Kong, China.
| | - Ka-On Lam
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 1/F, Professorial Block, 102 Pokfulam Road, Hong Kong, China.
| | - Pui-Mei Lam
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 1/F, Professorial Block, 102 Pokfulam Road, Hong Kong, China.
| | - To-Wai Leung
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 1/F, Professorial Block, 102 Pokfulam Road, Hong Kong, China.
| | - Dora L W Kwong
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 1/F, Professorial Block, 102 Pokfulam Road, Hong Kong, China.
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Patterson SE, Liu R, Statz CM, Durkin D, Lakshminarayana A, Mockus SM. The clinical trial landscape in oncology and connectivity of somatic mutational profiles to targeted therapies. Hum Genomics 2016; 10:4. [PMID: 26772741 PMCID: PMC4715272 DOI: 10.1186/s40246-016-0061-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 01/10/2016] [Indexed: 12/24/2022] Open
Abstract
Background Precision medicine in oncology relies on rapid associations between patient-specific variations and targeted therapeutic efficacy. Due to the advancement of genomic analysis, a vast literature characterizing cancer-associated molecular aberrations and relative therapeutic relevance has been published. However, data are not uniformly reported or readily available, and accessing relevant information in a clinically acceptable time-frame is a daunting proposition, hampering connections between patients and appropriate therapeutic options. One important therapeutic avenue for oncology patients is through clinical trials. Accordingly, a global view into the availability of targeted clinical trials would provide insight into strengths and weaknesses and potentially enable research focus. However, data regarding the landscape of clinical trials in oncology is not readily available, and as a result, a comprehensive understanding of clinical trial availability is difficult. Results To support clinical decision-making, we have developed a data loader and mapper that connects sequence information from oncology patients to data stored in an in-house database, the JAX Clinical Knowledgebase (JAX-CKB), which can be queried readily to access comprehensive data for clinical reporting via customized reporting queries. JAX-CKB functions as a repository to house expertly curated clinically relevant data surrounding our 358-gene panel, the JAX Cancer Treatment Profile (JAX CTP), and supports annotation of functional significance of molecular variants. Through queries of data housed in JAX-CKB, we have analyzed the landscape of clinical trials relevant to our 358-gene targeted sequencing panel to evaluate strengths and weaknesses in current molecular targeting in oncology. Through this analysis, we have identified patient indications, molecular aberrations, and targeted therapy classes that have strong or weak representation in clinical trials. Conclusions Here, we describe the development and disseminate system methods for associating patient genomic sequence data with clinically relevant information, facilitating interpretation and providing a mechanism for informing therapeutic decision-making. Additionally, through customized queries, we have the capability to rapidly analyze the landscape of targeted therapies in clinical trials, enabling a unique view into current therapeutic availability in oncology.
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Affiliation(s)
- Sara E Patterson
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | - Rangjiao Liu
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | - Cara M Statz
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | - Daniel Durkin
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
| | | | - Susan M Mockus
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Dr., Farmington, CT, 06032, USA.
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