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Lin GB, Chen WT, Kuo YY, Liu HH, Chen YM, Leu SJ, Chao CY. Thermal cycling‑hyperthermia sensitizes non‑small cell lung cancer A549 cells to EGFR tyrosine kinase inhibitor erlotinib. Oncol Rep 2025; 53:58. [PMID: 40183398 PMCID: PMC11976370 DOI: 10.3892/or.2025.8891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Molecular targeted therapy has emerged as a mainstream treatment for non‑small cell lung cancer (NSCLC), the most common type of lung cancer and the leading cause of cancer‑related death in both men and women. Erlotinib (Erl), a targeted therapy inhibiting EGFR pathways, has shown notable response rate in NSCLC cells. However, limited efficacy of the treatment has been reported due to resistance among a proportion of patients with NSCLC. Therefore, sensitizers are required to potentiate the efficacy of Erl in NSCLC treatment. The present study proposed a novel thermal therapy, thermal cycling‑hyperthermia (TC‑HT), as a supplement to amplify the effects of Erl. It was demonstrated that TC‑HT reduced the half‑maximal inhibitory concentration of Erl to 0.5 µM and TC‑HT sensitized A549 NSCLC cells to Erl via the downstream EGFR signaling cascades. Furthermore, the combination treatment of Erl and TC‑HT induced G2/M cell cycle arrest and inhibition of cell proliferation and migration. In addition, by slightly raising the temperature of TC‑HT, TC‑HT treatment alone produced antineoplastic effects without damaging the normal IMR‑90 lung cells. The method presented in this study may be applicable to other combination therapies and could potentially act as a starter for anticancer treatments, with fewer side effects.
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Affiliation(s)
- Guan-Bo Lin
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
| | - Wei-Ting Chen
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
| | - Yu-Yi Kuo
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
| | - Hsu-Hsiang Liu
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
- Graduate Institute of Applied Physics, Biophysics Division, National Taiwan University, Taipei 106319, Taiwan, R.O.C
| | - You-Ming Chen
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
- Graduate Institute of Applied Physics, Biophysics Division, National Taiwan University, Taipei 106319, Taiwan, R.O.C
| | - Shr-Jeng Leu
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan, R.O.C
| | - Chih-Yu Chao
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
- Graduate Institute of Applied Physics, Biophysics Division, National Taiwan University, Taipei 106319, Taiwan, R.O.C
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Heymach JV, Yu HA, Besse B, Cheng Y, Tan DSW, Wei L, Wacheck V, Nishio M. REZILIENT3: randomized phase III study of first-line zipalertinib plus chemotherapy in patients with EGFR exon 20 insertion-mutated NSCLC. Future Oncol 2025; 21:549-556. [PMID: 39957151 PMCID: PMC11845107 DOI: 10.1080/14796694.2025.2457294] [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: 10/30/2024] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
There remains a significant unmet need for effective and tolerable treatments for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations in the first-line setting. First and later generation EGFR tyrosine kinase inhibitors (TKIs) have shown efficacy for common EGFR mutations; however, their effectiveness against ex20ins mutations is limited, and platinum-based chemotherapy remains part of the standard of care. Data suggest that combining chemotherapy with EGFR inhibitors offers promise for EGFR ex20ins-mutated NSCLC. REZILIENT3 is an ongoing phase III study evaluating the efficacy and safety of zipalertinib (an orally available, irreversible EGFR-TKI) plus first-line standard-of-care platinum-based chemotherapy with chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations.Clinical Trial Registration: NCT05973773 (ClinicalTrials.gov).
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Affiliation(s)
- John V. Heymach
- Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Helena A. Yu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Benjamin Besse
- Department of Cancer Medicine, Institut Gustave Roussy, Paris-Saclay University, Villejuif, France
| | - Ying Cheng
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China
| | - Daniel SW. Tan
- Division of Medical Oncology, National Cancer Center Singapore, Duke-NUS Medical School, Singapore
| | - Li Wei
- Clinical Development, Taiho Oncology, Inc, Princeton, NJ, USA
| | - Volker Wacheck
- Clinical Development, Taiho Oncology, Inc, Princeton, NJ, USA
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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Ma L, Zhang J, Dai Z, Liao P, Guan J, Luo Z. Top 100 most-cited articles on apoptosis of non-small cell lung cancer over the past two decades: a bibliometrics analysis. Front Immunol 2025; 15:1512349. [PMID: 39872524 PMCID: PMC11770037 DOI: 10.3389/fimmu.2024.1512349] [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: 10/16/2024] [Accepted: 12/09/2024] [Indexed: 01/30/2025] Open
Abstract
Background Recently there has been an increasing number of studies have explored apoptosis mechanisms in lung cancer (LC). However, no researchers have conducted a bibliometric analysis of the most cited articles in this field. Objective To examine the top 100 most influential and cited publications on apoptosis in non-small cell lung cancer (NSCLC) from 2004 to 2023, summarizing research trends and key focus areas. Methods This study utilized the Web of Science Core Database (WOSCC) to research NSCLC apoptosis from 2004 to 2023, using keyword selection and manual screening for article searches. Bibliometrix package of R software 4.3.1 was used to generate distribution statistics for the top ten institutions, journals and authors. Citespace6.2. R6 was used to create the visualization maps for keyword co-occurrence and clustering. VOSviewer1.6.19 was used to conduct cluster analysis of publishing countries (regions), with data exported to SCImago Graphica for geographic visualization and cooperation analysis. VOSviewer1.6.19 was used to produced co-citation maps of institutions, journals, authors, and references. Results From 2004 to 2023, 13316 articles were retrieved, and the top 100 most cited were chosen. These were authored by 934 individuals from 269 institutions across 18 countries and appeared in 45 journals. Citations ranged from 150 to 1,389, with a median of 209.5. The most influential articles appeared in 2005 and 2007 (n=13). The leading countries (regions), institutions, journals and authors were identified as the United States (n=60), Harvard University (n=64), CANCER RESEARCH (n=15), SUN M and YANG JS (n=6). The top five keywords were "expression", "activation", "apoptosis", "pathway" and "gefitinib". This study indicates that enhancing apoptosis through circular RNA regulation and targeting the Nrf2 signaling pathway could become a key research focus in recent years. Conclusion Apoptosis has been the subject of extensive research over many years, particularly in relation to its role in the pathogenesis, diagnosis, and treatment of NSCLC. This study aims to identify highly influential articles and forecast emerging research trends, thereby offering insights into novel therapeutic targets and strategies to overcome drug resistance. The findings are intended to serve as a valuable reference for scholars engaged in this field of study.
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Affiliation(s)
- Leshi Ma
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Zhang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zi Dai
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Pei Liao
- Department of Oncology, Chongqing Hospital, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Chongqing, China
| | - Jieshan Guan
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Shenshan Hospital, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Shanwei, China
| | - Zhijie Luo
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
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Yu JZ, Kiss Z, Ma W, Liang R, Li T. Preclinical Models for Functional Precision Lung Cancer Research. Cancers (Basel) 2024; 17:22. [PMID: 39796653 PMCID: PMC11718887 DOI: 10.3390/cancers17010022] [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: 11/15/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Patient-centered precision oncology strives to deliver individualized cancer care. In lung cancer, preclinical models and technological innovations have become critical in advancing this approach. Preclinical models enable deeper insights into tumor biology and enhance the selection of appropriate systemic therapies across chemotherapy, targeted therapies, immunotherapies, antibody-drug conjugates, and emerging investigational treatments. While traditional human lung cancer cell lines offer a basic framework for cancer research, they often lack the tumor heterogeneity and intricate tumor-stromal interactions necessary to accurately predict patient-specific clinical outcomes. Patient-derived xenografts (PDXs), however, retain the original tumor's histopathology and genetic features, providing a more reliable model for predicting responses to systemic therapeutics, especially molecularly targeted therapies. For studying immunotherapies and antibody-drug conjugates, humanized PDX mouse models, syngeneic mouse models, and genetically engineered mouse models (GEMMs) are increasingly utilized. Despite their value, these in vivo models are costly, labor-intensive, and time-consuming. Recently, patient-derived lung cancer organoids (LCOs) have emerged as a promising in vitro tool for functional precision oncology studies. These LCOs demonstrate high success rates in growth and maintenance, accurately represent the histology and genomics of the original tumors and exhibit strong correlations with clinical treatment responses. Further supported by advancements in imaging, spatial and single-cell transcriptomics, proteomics, and artificial intelligence, these preclinical models are reshaping the landscape of drug development and functional precision lung cancer research. This integrated approach holds the potential to deliver increasingly accurate, personalized treatment strategies, ultimately enhancing patient outcomes in lung cancer.
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Affiliation(s)
- Jie-Zeng Yu
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (J.-Z.Y.); (Z.K.); (W.M.); (R.L.)
| | - Zsofia Kiss
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (J.-Z.Y.); (Z.K.); (W.M.); (R.L.)
| | - Weijie Ma
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (J.-Z.Y.); (Z.K.); (W.M.); (R.L.)
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Ruqiang Liang
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (J.-Z.Y.); (Z.K.); (W.M.); (R.L.)
| | - Tianhong Li
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (J.-Z.Y.); (Z.K.); (W.M.); (R.L.)
- Medical Service, Hematology/Oncology, Veterans Affairs Northern California Health Care System, Mather, CA 10535, USA
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Ivanina Foureau AV, Foureau DM, McHale CC, Guo F, Farhangfar CJ, Mileham KF. Phosphodiesterase Inhibition to Sensitize Non-Small-Cell Lung Cancer to Pemetrexed: A Double-Edged Strategy. Cancers (Basel) 2024; 16:2475. [PMID: 39001537 PMCID: PMC11240499 DOI: 10.3390/cancers16132475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/01/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024] Open
Abstract
Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDEmut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDEwt NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses.
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Affiliation(s)
- Anna V Ivanina Foureau
- Translational Research, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA
| | - David M Foureau
- Immune Monitoring Core Laboratory, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA
| | - Cody C McHale
- Molecular Targeted Therapeutics Laboratory, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA
| | - Fei Guo
- Immune Monitoring Core Laboratory, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA
| | - Carol J Farhangfar
- Translational Research, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA
| | - Kathryn F Mileham
- Thoracic Medical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA
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Nammalwar B, Bunce RA. Recent Advances in Pyrimidine-Based Drugs. Pharmaceuticals (Basel) 2024; 17:104. [PMID: 38256937 PMCID: PMC10820437 DOI: 10.3390/ph17010104] [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: 11/27/2023] [Revised: 01/03/2024] [Accepted: 01/07/2024] [Indexed: 01/24/2024] Open
Abstract
Pyrimidines have become an increasingly important core structure in many drug molecules over the past 60 years. This article surveys recent areas in which pyrimidines have had a major impact in drug discovery therapeutics, including anti-infectives, anticancer, immunology, immuno-oncology, neurological disorders, chronic pain, and diabetes mellitus. The article presents the synthesis of the medicinal agents and highlights the role of the biological target with respect to the disease model. Additionally, the biological potency, ADME properties and pharmacokinetics/pharmacodynamics (if available) are discussed. This survey attempts to demonstrate the versatility of pyrimidine-based drugs, not only for their potency and affinity but also for the improved medicinal chemistry properties of pyrimidine as a bioisostere for phenyl and other aromatic π systems. It is hoped that this article will provide insight to researchers considering the pyrimidine scaffold as a chemotype in future drug candidates in order to counteract medical conditions previously deemed untreatable.
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Affiliation(s)
- Baskar Nammalwar
- Vividion Therapeutics, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA;
| | - Richard A. Bunce
- Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA
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Mao YZ, Xi XX, Zhao HY, Zhang YL, Zhang SQ. Design, synthesis and evaluation of new pyrimidine derivatives as EGFR C797S tyrosine kinase inhibitors. Bioorg Med Chem Lett 2023; 91:129381. [PMID: 37336419 DOI: 10.1016/j.bmcl.2023.129381] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/02/2023] [Accepted: 06/14/2023] [Indexed: 06/21/2023]
Abstract
The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFRC797S mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFRC797S-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFRdel19/T790M/C797S) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFRdel19/T790M/C797S. Based on these results, A5 turned out to be effective reversible EGFRC797S-TKIs which can be further developed.
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Affiliation(s)
- Yu-Ze Mao
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Xiao-Xiao Xi
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Hong-Yi Zhao
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Yin-Liang Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - San-Qi Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China.
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Bortnevskaya YS, Shiryaev NA, Zakharov NS, Kitoroage OO, Gradova MA, Karpechenko NY, Novikov AS, Nikolskaya ED, Mollaeva MR, Yabbarov NG, Bragina NA, Zhdanova KA. Synthesis and Biological Properties of EGFR-Targeted Photosensitizer Based on Cationic Porphyrin. Pharmaceutics 2023; 15:pharmaceutics15041284. [PMID: 37111769 PMCID: PMC10145264 DOI: 10.3390/pharmaceutics15041284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/13/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
Photodynamic therapy (PDT) in oncology is characterized by low invasiveness, minimal side effects, and little tissue scarring. Increasing the selectivity of PDT agents toward a cellular target is a new approach intended to improve this method. This study is devoted to the design and synthesis of a new conjugate based on meso-arylporphyrin with a low-molecular-weight tyrosine kinase inhibitor, Erlotinib. A nano-formulation based on Pluronic F127 micelles was obtained and characterized. The photophysical and photochemical properties and biological activity of the studied compounds and their nano-formulation were studied. A significant, 20-40-fold difference between the dark and photoinduced activity was achieved for the conjugate nanomicelles. After irradiation, the studied conjugate nanomicelles were 1.8 times more toxic toward the EGFR-overexpressing cell line MDA-MB-231 compared to the conditionally normal NKE cells. The IC50 was 0.073 ± 0.014 μM for the MDA-MB-231 cell line and 0.13 ± 0.018 μM for NKE cells after irradiation for the target conjugate nanomicelles.
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Affiliation(s)
- Yulia S Bortnevskaya
- Institute of Fine Chemical Technology, MIREA-Russian Technological University, Vernadsky pr., 86, 119571 Moscow, Russia
| | - Nikita A Shiryaev
- Institute of Fine Chemical Technology, MIREA-Russian Technological University, Vernadsky pr., 86, 119571 Moscow, Russia
| | - Nikita S Zakharov
- Institute of Fine Chemical Technology, MIREA-Russian Technological University, Vernadsky pr., 86, 119571 Moscow, Russia
| | - Oleg O Kitoroage
- Institute of Fine Chemical Technology, MIREA-Russian Technological University, Vernadsky pr., 86, 119571 Moscow, Russia
| | - Margarita A Gradova
- N. N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, Kosygin St., 4, 119991 Moscow, Russia
| | - Natalia Yu Karpechenko
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Highway, 24, 115522 Moscow, Russia
- Department of Medical Chemistry and Toxicology, Pirogov National Research Medical University, Ministry of Health of Russia, Ostrovityanova St., 1, 117997 Moscow, Russia
| | - Alexander S Novikov
- Institute of Chemistry, Saint Petersburg State University, Universitetskaya nab. 7-9, 199034 Saint Petersburg, Russia
- Research Institute of Chemistry, Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, 117198 Moscow, Russia
| | - Elena D Nikolskaya
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygina St., 4, 119334 Moscow, Russia
| | - Mariia R Mollaeva
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygina St., 4, 119334 Moscow, Russia
| | - Nikita G Yabbarov
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygina St., 4, 119334 Moscow, Russia
| | - Natal'ya A Bragina
- Institute of Fine Chemical Technology, MIREA-Russian Technological University, Vernadsky pr., 86, 119571 Moscow, Russia
| | - Kseniya A Zhdanova
- Institute of Fine Chemical Technology, MIREA-Russian Technological University, Vernadsky pr., 86, 119571 Moscow, Russia
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Wang H, Xing R, Li M, Zhang M, Wei C, Zhang G, Niu Y, Ma Z, Yan X. Clinical efficacy and prognosis analysis of treatment regimens for EGFR mutant non-small cell lung cancer and brain metastasis: a retrospective study. BMC Cancer 2023; 23:289. [PMID: 36997925 PMCID: PMC10061743 DOI: 10.1186/s12885-023-10744-2] [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: 11/03/2022] [Accepted: 03/16/2023] [Indexed: 04/01/2023] Open
Abstract
BACKGROUND The aims of the study were to evaluate potential differences among first-line treatment for EGFR mutant (m+) non-small cell lung cancer (NSCLC) patients with brain metastasis in China and to identify the factors influencing survival outcomes. METHODS In this retrospective study, 172 EGFRm + patients with advanced NSCLC who received a 1st generation EGFR tyrosine kinase inhibitor (TKI) were divided into 4 groups: A, EGFR-TKI (n = 84); B, EGFR-TKI + pemetrexed + cisplatin/carboplatin chemotherapy (CT) (n = 55); C, EGFR-TKI + bevacizumab (n = 15); and D, EGFR-TKI + pemetrexed + cisplatin/carboplatin CT + bevacizumab (n = 18). Intracranial and extracranial progression-free survival (PFS), the overall survival (OS), objective remission rates (ORRs) and adverse events were analyzed. RESULTS Intracranial PFS of groups C + D was longer than for groups A + B (18.9 m vs. 11.0 m, P = 0.027). Extracranial PFS were longer in group B in comparison with group A (13.0 m vs. 11.5 m, P = 0.039) and in groups C + D compared to groups A + B (18.9 m vs. 11.9 m, P = 0.008). Median OS in groups A and B were 27.9 m and 24.4 m, respectively, while groups C and D have not yet achieved median OS. Significant difference was found in intracranial ORR between groups A + B vs. C + D (31.0% vs. 65.2%, P = 0.002). Most patients suffered grade 1-2 treatment-related adverse events, which were relieved soon after symptomatic treatment. CONCLUSIONS First-generation EGFR-TKI + bevacizumab treatment outperformed other regimens in EGFRm + NSCLC patients with brain metastasis. The therapy improved the control and delayed progression of intracranial lesions and prolonged survival times.
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Affiliation(s)
- Huijuan Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China.
| | - Ruyue Xing
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
| | - Mengmeng Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
| | - Mina Zhang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
| | - Chunhua Wei
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
| | - Guowei Zhang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
| | - Yuanyuan Niu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
| | - Zhiyong Ma
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
| | - Xiangtao Yan
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450000, China
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Basu D, Pal R, Sarkar M, Barma S, Halder S, Roy H, Nandi S, Samadder A. To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors. Curr Top Med Chem 2023; 23:2877-2972. [PMID: 38164722 DOI: 10.2174/0115680266261150231110053650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 01/03/2024]
Abstract
Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.
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Affiliation(s)
- Debroop Basu
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Riya Pal
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, IndiaIndia
| | - Maitrayee Sarkar
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Soubhik Barma
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sumit Halder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Harekrishna Roy
- Nirmala College of Pharmacy, Vijayawada, Guntur, Andhra Pradesh, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
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Wu Y, Du B, Lv C, Ji X, Lan Y, Yao N, Zhu Y, Lai J. First-generation EGFR-TKI plus bevacizumab and chemotherapy for advanced EGFR-mutated non-squamous non-small-cell lung cancer: a retrospective study. Ann Med 2023; 55:2243967. [PMID: 37557185 PMCID: PMC10413910 DOI: 10.1080/07853890.2023.2243967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/30/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND This study aimed to compare the efficacy and safety of different treatment modalities for previously untreated advanced EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC). METHODS This retrospective study included 196 advanced EGFR-mutated non-squamous NSCLC. 107 received EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy (T), 53 received EGFR-TKI + bevacizumab (T + A), and 36 received EGFR-TKI + bevacizumab + chemotherapy (T + A + C). The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS The median PFS was 27 months in the T + A + C group, 17 months in the T + A group, and 10 months in the T group. The multivariate analysis showed lower disease progression in the T + A + C group (HR, 0.377; 95% CI, 0.224-0.634; p < .001). Subgroup analysis showed that the T + A + C group did significantly improve PFS in patients with metastatic organs ≥2, brain metastases, liver metastases, and EGFR 19del compared to T + A group. No significant improvement in OS in the T + A + C group versus the T + A group, but a significant benefit in the subgroup of patients with metastatic organs ≥2. We also performed a subgroup analysis of the T + A + C group versus the T group, which similarly showed that the T + A + C group had better PFS than the T group in most subgroups, and the T + A + C group significantly improved OS in patients with metastatic organ ≥2 and liver metastases compared with the T group. The ORR was significantly higher in the T + A + C group than A + T and T groups (83.3% vs 71.7% vs 60.7%, p = .033). In safety, the T + A + C group had a higher incidence of AEs, but the majority was grade 1-2. The most frequent AEs of grade ≥ 3 were leukopenia (8.3%) and increased aminotransferase (8.3%) in the T + A + C group. CONCLUSIONS First-generation EGFR-TKI plus bevacizumab plus chemotherapy was a promising strategy for advanced EGFR-mutated non-squamous NSCLC.
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Affiliation(s)
- Yahua Wu
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Bin Du
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Chengliu Lv
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Xiaohui Ji
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yanqin Lan
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Na Yao
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yingjiao Zhu
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Jinhuo Lai
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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Gijtenbeek RG, van der Noort V, Aerts JG, Staal-van den Brekel JA, Smit EF, Krouwels FH, Wilschut FA, Hiltermann TJN, Timens W, Schuuring E, Janssen JD, Goosens M, van den Berg PM, de Langen AJ, Stigt JA, van den Borne BE, Groen HJ, van Geffen WH, van der Wekken AJ. Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer. ERJ Open Res 2022; 8:00239-2022. [PMID: 36267895 PMCID: PMC9574558 DOI: 10.1183/23120541.00239-2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/05/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.
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Affiliation(s)
- Rolof G.P. Gijtenbeek
- Dept of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
| | - Vincent van der Noort
- Dept of Biometrics, Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - Joachim G.J.V. Aerts
- Dept of Pulmonary Diseases, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | | | - Egbert F. Smit
- Dept of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Frans H. Krouwels
- Dept of Respiratory Medicine, Spaarne Hospital, Hoofddorp, The Netherlands
| | - Frank A. Wilschut
- Dept of Respiratory Medicine, Gelderse Vallei Hospital, Ede, The Netherlands
| | - T. Jeroen N. Hiltermann
- Dept of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Wim Timens
- Dept of Pathology and Medical Biology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Ed Schuuring
- Dept of Pathology and Medical Biology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Joost D.J. Janssen
- Dept of Respiratory Medicine, Máxima Medical Centre, Eindhoven/Veldhoven, The Netherlands
| | - Martijn Goosens
- Dept of Pulmonary Medicine, Gelre Hospitals, Zutphen, The Netherlands
| | | | - A. Joop de Langen
- Dept of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos A. Stigt
- Dept of Respiratory Medicine, Isala Hospital, Zwolle, The Netherlands
| | | | - Harry J.M. Groen
- Dept of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Wouter H. van Geffen
- Dept of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
| | - Anthonie J. van der Wekken
- Dept of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
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Sun SJ, Han JD, Liu W, Wu ZY, Zhao X, Yan X, Jiao SC, Fang J. Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer. World J Clin Cases 2022; 10:6069-6081. [PMID: 35949840 PMCID: PMC9254173 DOI: 10.12998/wjcc.v10.i18.6069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/13/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).
AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.
METHODS This multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups.
RESULTS The median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05).
CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.
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Affiliation(s)
- Sheng-Jie Sun
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jin-Di Han
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
| | - Wei Liu
- Peking Cancer Hospital Palliative Care Center, Beijing Cancer Hospital, Beijing 100142, China
| | - Zhi-Yong Wu
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiao Zhao
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiang Yan
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Shun-Chang Jiao
- Department of Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jian Fang
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
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Nottingham E, Mazzio E, Surapaneni SK, Kutlehria S, Mondal A, Badisa R, Safe S, Rishi AK, Singh M. Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells. J Pharm Anal 2021; 11:799-807. [PMID: 35028186 PMCID: PMC8740161 DOI: 10.1016/j.jpha.2021.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/04/2021] [Accepted: 06/09/2021] [Indexed: 11/09/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is often characterized by an underlying mutation in the epidermal growth factor receptor (EGFR), contributing to aggressive metastatic disease. Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate (CDODA-Me), a glycyrrhetinic acid derivative, reportedly improves the therapeutic response to erlotinib (ERL), an EGFR tyrosine kinase inhibitor. In the present study, we performed a series of studies to demonstrate the efficacy of CDODA-Me (2 μM) in sensitizing HCC827R (ERL-resistant) cells to ERL. Herein, we first established the selectivity of ERL-induced drug resistance in the HCC827R cells, which was sensitized when ERL was combined with CDODA-Me (2 μM), shifting the IC50 from 23.48 μM to 5.46 μM. Subsequently, whole transcriptomic microarray expression data demonstrated that the combination of ERL + CDODA-Me elicited 210 downregulated genes (0.44% of the whole transcriptome (WT)) and 174 upregulated genes (0.36% of the WT), of which approximately 80% were unique to the ERL + CDODA-Me group. Synergistic effects centered on losses to cell cycle progression transcripts, a reduction of minichromosome maintenance complex components (MCM2-7), all key components of the Cdc45·MCM2-7GINS (CMG) complex, and replicative helicases; these effects were tantamount to the upregulation of processes associated with the nuclear factor erythroid 2 like 2 translational response to oxidative stress, including sulfiredoxin 1, heme oxygenase 1, and stress-induced growth inhibitor 1. Collectively, these findings indicate that the synergistic therapeutic effects of ERL + CDODA-Me on resistant NSCLC cells are mediated via the inhibition of mitosis and induction of oxidative stress.
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Affiliation(s)
- Ebony Nottingham
- Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA
| | - Elizabeth Mazzio
- Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA
| | - Sunil Kumar Surapaneni
- Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA
| | - Shallu Kutlehria
- Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA
| | - Arindam Mondal
- Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA
| | - Ramesh Badisa
- Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A & M University, College Station, TX, 77843, USA
| | - Arun K. Rishi
- John D. Dingell VA medical Center and Department of Oncology, Wayne State University, Detroit, MI, 48201, USA
| | - Mandip Singh
- Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA
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Papini F, Sundaresan J, Leonetti A, Tiseo M, Rolfo C, Peters GJ, Giovannetti E. Hype or hope - Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC? Crit Rev Oncol Hematol 2021; 166:103454. [PMID: 34455092 DOI: 10.1016/j.critrevonc.2021.103454] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 02/08/2023] Open
Abstract
Three generations of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) have been developed for treating advanced/metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations, while a fourth generation is undergoing preclinical assessment. Although initially effective, acquired resistance to EGFR-TKIs usually arises within a year due to the emergence of clones harboring multiple resistance mechanisms. Therefore, the combination of EGFR-TKIs with other therapeutic agents has emerged as a potential strategy to overcome resistance and improve clinical outcomes. However, results obtained so far are ambiguous and ideal therapies for patients who experience disease progression during treatment with EGFR-TKIs remain elusive. This review provides an updated landscape of EGFR-TKIs, along with a description of the mechanisms causing resistance to these drugs. Moreover, it discusses the current knowledge, limitations, and future perspective regarding the use of EGFR-TKIs in combination with other anticancer agents, supporting the need for bench-to-bedside approaches in selected populations.
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Affiliation(s)
- Filippo Papini
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy
| | - Janani Sundaresan
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Alessandro Leonetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Christian Rolfo
- The Center of Thoracic Oncology at the Tisch Cancer Institute, Mount Sinai, NYC, United States
| | - Godefridus J Peters
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Biochemistry, Medical University of Gdansk, Poland
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy.
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Das D, Wang J, Hong J. Next-Generation Kinase Inhibitors Targeting Specific Biomarkers in Non-Small Cell Lung Cancer (NSCLC): A Recent Overview. ChemMedChem 2021; 16:2459-2479. [PMID: 33929777 DOI: 10.1002/cmdc.202100166] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/27/2021] [Indexed: 12/25/2022]
Abstract
Lung cancer causes many deaths globally. Mutations in regulatory genes, irregularities in specific signal transduction events, or alterations of signalling pathways are observed in cases of non-small cell lung cancer (NSCLC). Over the past two decades, a few kinases have been identified, validated, and studied as biomarkers for NSCLC. Among them, EGFR, ALK, ROS1, MET, RET, NTRK, and BRAF are regarded as targetable biomarkers to cure and/or control the disease. In recent years, the US Food and Drug Administration (FDA) approved more than 15 kinase inhibitors targeting these NSCLC biomarkers. The kinase inhibitors significantly improved the progression-free survival (PFS) of NSCLC patients. Challenges still remain for metastatic diseases and advanced NSCLC cases. New discoveries of potent kinase inhibitors and rapid development of modern medical technologies will help to control NSCLC cases. This article provides an overview of the discoveries of various types of kinase inhibitors against NSCLC, along with medicinal chemistry aspects and related developments in next-generation kinase inhibitors that have been reported in recent years.
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Affiliation(s)
- Debasis Das
- Discovery Chemistry Research, Arromax Pharmatech Co., Ltd., Sangtiandao Innovation Park, No. 1 Huayun Road, SIP, Suzhou, 215123, China
| | - Jingbing Wang
- Discovery Chemistry Research, Arromax Pharmatech Co., Ltd., Sangtiandao Innovation Park, No. 1 Huayun Road, SIP, Suzhou, 215123, China
| | - Jian Hong
- Discovery Chemistry Research, Arromax Pharmatech Co., Ltd., Sangtiandao Innovation Park, No. 1 Huayun Road, SIP, Suzhou, 215123, China
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Wang Q, Gao W, Gao F, Jin S, Qu T, Lin F, Zhang C, Zhang J, Zhang Z, Chen L, Guo R. Efficacy and acquired resistance of EGFR-TKI combined with chemotherapy as first-line treatment for Chinese patients with advanced non-small cell lung cancer in a real-world setting. BMC Cancer 2021; 21:602. [PMID: 34034713 PMCID: PMC8152122 DOI: 10.1186/s12885-021-08291-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 05/04/2021] [Indexed: 12/24/2022] Open
Abstract
Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting. Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity. Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.67–23.33] vs. 11.70 months [95% CI, 10.81–12.59], p < 0.001). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.30–41.70) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08291-9.
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Affiliation(s)
- Qianqian Wang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Wen Gao
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Fangyan Gao
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Shidai Jin
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Tianyu Qu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Fan Lin
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101Longmian Avenue, Nanjing, 211166, Jiangning, China
| | - Chen Zhang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Jingya Zhang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Zhihong Zhang
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Liang Chen
- Department of Thoracic and Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Renhua Guo
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
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Wu Q, Luo W, Li W, Wang T, Huang L, Xu F. First-Generation EGFR-TKI Plus Chemotherapy Versus EGFR-TKI Alone as First-Line Treatment in Advanced NSCLC With EGFR Activating Mutation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Oncol 2021; 11:598265. [PMID: 33928022 PMCID: PMC8076535 DOI: 10.3389/fonc.2021.598265] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/04/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE The aim of this meta-analysis was to evaluate efficacy and toxicity of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in combination with chemotherapy (CT) compared to EGFR-TKI monotherapy as first-line treatment in advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutation. METHODS A systematic literature search of randomized controlled trials using Cochrane Library, PubMed, Embase, and Web of Science, was performed up to Jan. 7th, 2020. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated as effect values for progress-free survival (PFS) and overall survival (OS). Risk ratio (RR) and Odds ratio (OR) were calculated as effect values for objective response rate (ORR) and toxicity, respectively. RESULTS A total of eight randomized trials involving 1,349 advanced NSCLC patients with sensitive EGFR mutation were included in the meta-analysis. All patients in both groups received first-generation TKI as first-line treatment. The pooled HR of PFS and OS was 0.56 (95% CI = 0.50-0.64; P <0.00001) and 0.70 (95% CI = 0.54-0.90; P = 0.005), respectively. Subgroup analysis showed significantly higher OS advantages in patients receiving doublet CT (P = 0.02) and concurrent therapy (P = 0.002). The ORR in the EGFR-TKI plus CT group was significantly higher than in the EGFR-TKI monotherapy group (RR = 1.18, 95% CI = 1.10-1.26). The combination regimen showed a higher incidence of chemotherapy-induced toxicities. Subgroup analysis indicated that doublet chemotherapy rather than single-agent chemotherapy significantly increased incidence of grade 3 or higher leukopenia, neutropenia and anemia. CONCLUSIONS Compared with EGFR-TKI monotherapy, the combination of first-generation EGFR-TKI and CT, especially when applying concurrent delivery of platinum-based doublet chemotherapeutic drugs, significantly improve ORR and prolong PFS and OS in first-line treatment for advanced EGFR-mutated NSCLC. Although increasing incidence of chemotherapy-induced toxicities occurs in the combination group, it is well tolerated and clinically manageable.
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Affiliation(s)
- Qiang Wu
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Wuxia Luo
- Department of Oncology, Chengdu First People’s Hospital, Chengdu, China
| | - Wen Li
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Wang
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Huang
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Feng Xu
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
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Gao R, Zhang Y, Hou W, Li J, Zhu G, Zhang X, Xu B, Wu Z, Wang H. Combination of first-line chemotherapy with Kanglaite injections versus first-line chemotherapy alone for advanced non-small-cell lung cancer: study protocol for an investigator-initiated, multicenter, open-label, randomized controlled trial. Trials 2021; 22:214. [PMID: 33731199 PMCID: PMC7966914 DOI: 10.1186/s13063-021-05169-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 03/04/2021] [Indexed: 12/24/2022] Open
Abstract
Background Non-small-cell lung cancer (NSCLC) is usually diagnosed at an advanced stage, and chemotherapy is the main treatment for this disease. Kanglaite injections (KLTi) have been widely used for the treatment of cancer in China. KLTi combined with chemotherapy could improve the short-term efficacy, quality of life, and performance status for NSCLC compared with chemotherapy alone. This trial aims to assess the long-term efficacy and safety of KLTi in combination with chemotherapy for the treatment of advanced NSCLC. Methods This will be an investigator-initiated multicenter open-label randomized controlled trial. We will randomly assign 334 eligible participants with stage IIIA-IV NSCLC to the treatment or control groups in a 1:1 ratio. Patients in both groups will be administered 4–6 cycles of first-line platinum-based double chemotherapy regimens. Patients with complete response, partial response, or stable disease after 4–6 cycles will receive non-platinum single-agent chemotherapy. Patients in the treatment group are to receive intravenous KLTi 200 ml per day continuously for 14 days, commencing on the first day of chemotherapy. The treatment will be discontinued at the time of disease progression or until unacceptable toxicity is noted. The follow-up will be conducted every 2 months until death, loss of follow-up, or 12 months from randomized enrollment. The primary outcome will be progression-free survival (PFS). The secondary outcomes will be the objective response rate, 1-year survival rate, quality of life, living ability, and blood lipids. The safety outcome will be the rate of adverse events. Discussion This study will be the first randomized controlled trial in which PFS is used as the primary outcome to test whether KLTi combined with first-line chemotherapy has superior efficacy and reduced toxicity compared to chemotherapy alone in advanced NSCLC. This will also be the first clinical study to observe the effects of KLTi on blood lipids. Trial registration ClinicalTrials.gov NCT03986528. Prospectively registered on 30 May 2019.
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Affiliation(s)
- Ruike Gao
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,China Academy of Chinese Medical Sciences, Beijing, China
| | - Ying Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei Hou
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jie Li
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Guanghui Zhu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoxiao Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,China Academy of Chinese Medical Sciences, Beijing, China
| | - Bowen Xu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Beijing University of Chinese Medicine, Beijing, China
| | - Zhe Wu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,China Academy of Chinese Medical Sciences, Beijing, China
| | - Heping Wang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,China Academy of Chinese Medical Sciences, Beijing, China
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20
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Kim ST, Hong JY, Lee J, Park JO, Lim HY, Kang WK, Park YS. Pemetrexed/Erlotinib as a Salvage Treatment in Patients with High EGFR-Expressing Metastatic Colorectal Cancer Following Failure of Standard Chemotherapy: A Phase II Single-Arm Prospective Study. Target Oncol 2021; 15:67-73. [PMID: 31820199 DOI: 10.1007/s11523-019-00691-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Despite new agents to treat metastatic colorectal cancer (CRC), patients eventually progress and additional therapies are needed. OBJECTIVE We intended to evaluate the combination of pemetrexed/erlotinib in patients with high epidermal growth factor receptor (EGFR)-expressing (2+ or 3 on immunohistochemistry) metastatic CRC who experienced disease progression after standard chemotherapy. PATIENTS AND METHODS We investigated pemetrexed and erlotinib (pemetrexed 500 mg/m2 on Day 1 and erlotinib 100 mg/m2 on Days 1-21) as a salvage treatment, given every 3 weeks, until disease progression or intolerable toxicity. The primary outcome was overall response rate (RR). RESULTS From May 2017 to April 2018, 29 metastatic CRC patients with high EGFR expression who had previously received standard therapies were enrolled into this trial. The regimen was well tolerated. Skin rash, vomiting, fatigue, and anorexia were common toxic effects but were mostly manageable and controllable side effects of grades 1 or 2 only. In an intent-to-treat analysis, three partial responses (PRs) were observed in enrolled patients, revealing an overall RR of 10.3%. This value supported the statistical hypothesis of this study. Fifteen patients had stable disease and the disease control rate (DCR) was 62.1%. All three patients who achieved a PR had a tumor EGFR expression of 3+. Among the eight patients with EGFR 3+ expression, the RR and DCR were 37.5% and 75.0%, respectively. CONCLUSION This phase II trial using pemetrexed/erlotinib in metastatic CRC with high EGFR expression met the primary endpoint of tumor response. TRIAL REGISTRATION This study was registered at ClinicalTrials.gov (number NCT03086538).
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Affiliation(s)
- Seung Tae Kim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Jung Yong Hong
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Jeeyun Lee
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Joon Oh Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Ho Young Lim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Won Ki Kang
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Young Suk Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
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21
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Cheng F, Peng X, Meng G, Pu Y, Luo K, He B. Poly(ester-thioether) microspheres co-loaded with erlotinib and α-tocopheryl succinate for combinational therapy of non-small cell lung cancer. J Mater Chem B 2021; 8:1728-1738. [PMID: 32022097 DOI: 10.1039/c9tb02840d] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Polymer microspheres are attracting wide attention in localized cancer therapy owing to the excellent biocompatibility and drug loading capacity, controllable biodegradation speeds, and minimized systemic toxicity. Herein, we presented poly(ester-thioether) microspheres, porous and nonporous, as drug depots for localized therapy of non-small cell lung cancer (NSCLC). Specifically, erlotinib and α-tocopheryl succinate (α-TOS), which are respectively an epidermal growth factor receptor (EGFR) inhibitor and mitochondria destabilizer, were efficiently loaded into porous and nonporous poly(ester-thioether) microspheres for the treatment of EGFR-overexpressing NSCLC (A549 cells). The poly(ester-thioether) microspheres significantly improved the bioavailability of both erlotinib and α-TOS in comparison to the free drug combination, realizing synergistic inhibition of A549 cells both in vitro and in vivo. The porous microspheres displayed faster degradation and drug release than the nonporous counterpart, thereby showing better anticancer efficacy. Overall, our study reported a new anticancer strategy of erlotinib and α-TOS combination for therapy of NSCLC, and established that poly(ester-thioether) microspheres could be a robust and biodegradable reservoir for drug delivery and localized cancer therapy.
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Affiliation(s)
- Furong Cheng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China. and Center for Translational Medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China
| | - Xinyu Peng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
| | - Guolong Meng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
| | - Yuji Pu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
| | - Kui Luo
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bin He
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
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22
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Madhukar G, Subbarao N. Current and Future Therapeutic Targets: A Review on Treating Head and Neck Squamous Cell Carcinoma. Curr Cancer Drug Targets 2020; 21:386-400. [PMID: 33372876 DOI: 10.2174/1568009620666201229120332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/03/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) continues to be a global public health burden even after a tremendous development in its treatment. It is a heterogeneous cancer of upper aero-digestive tract. The contemporary strategy to treat cancer is the use of anticancer drugs against proteins possessing abnormal expression. Targeted chemotherapy was found successful in HNSCC, but, there is still a stagnant improvement in the survival rates and high recurrence rates due to undesirable chemotherapy reactions, non-specificity of drugs, resistance against drugs and drug toxicity on non-cancerous tissues and cells. Various extensive studies lead to the identification of drug targets capable to treat HNSCC effectively. The current review article gives an insight into these promising anticancer targets along with knowledge of drugs under various phases of development. In addition, new potential targets that are not yet explored against HNSCC are also described. We believe that exploring and developing drugs against these targets might prove beneficial in treating HNSCC.
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Affiliation(s)
- Geet Madhukar
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Naidu Subbarao
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
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23
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Lou Y, Xu J, Zhang Y, Lu J, Chu T, Zhang X, Wang H, Zhong H, Zhang W, Han B. Chemotherapy Plus EGFR-TKI as First-Line Treatment Provides Better Survival for Advanced EGFR-Positive Lung Adenocarcinoma Patients: Updated Data and Exploratory In Vitro Study. Target Oncol 2020; 15:175-184. [PMID: 32170554 DOI: 10.1007/s11523-020-00708-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Previously, we demonstrated that treatment with gefitinib combined with pemetrexed plus carboplatin chemotherapy improved progression-free survival (PFS) compared to gefitinib or chemotherapy alone in lung adenocarcinoma patients with sensitizing EGFR mutations. OBJECTIVE In the present study, we updated the long-term overall survival (OS) of the combination therapy and the gefitinib groups. Furthermore, the possible mechanisms underlying the effects of combination therapy were investigated. PATIENTS AND METHODS Lung adenocarcinoma patients harboring sensitizing EGFR mutations received either gefitinib plus chemotherapy (n = 40) or gefitinib alone (n = 41), and long-term survival was assessed. The pharmacological interaction between gefitinib and pemetrexed was evaluated in the PC-9 lung adenocarcinoma cell line using a colorimetric assay for assessing cell metabolic activity (MTT assay). The influence of combined treatment with gefitinib plus pemetrexed on gene expression profiles and signaling pathways was investigated using microarrays and Ingenuity Pathway Analysis (IPA). RESULTS On the last day of follow-up (28 September 2018), 30 (75.0%) patients in the combination group and 35 (85.4%) patients in the gefitinib group had died. The 2-year and 3-year survival rates of the combination versus gefitinib were 85.0% versus 56.1% (P = 0.004) and 52.5% versus 24.4% (P = 0.009), respectively. The median OS was 37.9 months (95% CI: 17.3-58.6) for the combination group and 25.8 months (95% CI: 19.2-32.3) for the gefitinib group (HR = 0.56, 95% CI: 0.34-0.91, P = 0.02). A synergistic inhibitory effect between gefitinib and pemetrexed was observed in the lung adenocarcinoma cell line PC-9. Furthermore, widespread gene expression changes and critical signaling pathways such as AKT signaling were identified, which might be responsible for the synergism seen with the combination treatment. CONCLUSIONS Combined treatment with gefitinib plus pemetrexed resulted in improved OS over gefitinib alone. A synergistic inhibitory effect between gefitinib and pemetrexed was observed on lung adenocarcinoma cell growth. Gene expression profile analysis revealed potential signaling pathways, including AKT signaling, contributing to the synergism. CLINICAL TRIAL REGISTRATION NUMBER NCT02148380.
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Affiliation(s)
- Yuqing Lou
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Jianlin Xu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Yanwei Zhang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Jun Lu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Tianqing Chu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Xueyan Zhang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Huimin Wang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Hua Zhong
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Wei Zhang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China.
| | - Baohui Han
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China.
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24
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Boonsri B, Yacqub-Usman K, Thintharua P, Myint KZ, Sae-Lao T, Collier P, Suriyonplengsaeng C, Larbcharoensub N, Balasubramanian B, Venkatraman S, Egbuniwe IU, Gomez D, Mukherjee A, Kumkate S, Janvilisri T, Zaitoun AM, Kuakpaetoon T, Tohtong R, Grabowska AM, Bates DO, Wongprasert K. Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells. Cancer Res Treat 2020; 53:457-470. [PMID: 33070556 PMCID: PMC8053863 DOI: 10.4143/crt.2020.585] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/05/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. Results CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.
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Affiliation(s)
- Boonyakorn Boonsri
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kiren Yacqub-Usman
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Pakpoom Thintharua
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kyaw Zwar Myint
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Thannicha Sae-Lao
- Department of Anatomy, Faculty of Medicine, Siam University, Bangkok, Thailand
| | - Pam Collier
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | | | - Noppadol Larbcharoensub
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Brinda Balasubramanian
- Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Simran Venkatraman
- Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Isioma U Egbuniwe
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.,Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Dhanwant Gomez
- Department of Hepatobiliary and Pancreatic Surgery, and NIHR Nottingham Digestive Disease Biomedical Research Unit, University of Nottingham, Nottingham, UK
| | - Abhik Mukherjee
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.,Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Supeecha Kumkate
- Department of Biology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Abed M Zaitoun
- Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | | | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Anna M Grabowska
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - David O Bates
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
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25
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Pathak P, Naumovich V, Grishina M, Potemkin V. The study of EGFR-ligand complex electron property relationship with biological activity. J Biomol Struct Dyn 2020; 40:375-388. [PMID: 32897174 DOI: 10.1080/07391102.2020.1813629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The present investigation grounded on estimation of electron properties of the structures of EGFR proteins-ligand complexes using our laboratory-developed methodology AlteQ approach, which describes the molecular electron density of the complex in space for a certain point in three-dimensional coordinates. Briefly, the system embodies molecular electron density as a sum of Slater's type atomic increments of the molecular system. Further, using this methodology, we calculated different electron characteristics of selected EGFR protein-ligand complexes and established the relationship between different electron properties with their experimental pharmacological activity value (pIC50). The study suggested that EGFR inhibitory activity has higher correlation with intermolecular contacts of H with pi-system of aromatic ring between protein and ligands. Therefore, this created model has impact to identify and design potential ligands against EGFR in anticancer drug discovery.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Prateek Pathak
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia
| | - Vladislav Naumovich
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia
| | - Maria Grishina
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia
| | - Vladimir Potemkin
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia
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26
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Pan C, Duan H, Wu Y, Zhu C, Yi C, Duan Y, Lu D, Guo C, Wu D, Wang Y, Fu X, Xu J, Chen Y, Luo M, Tian W, Pan T, Xu W, Zhang S, Huang J. Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. Int J Oncol 2020; 57:939-955. [PMID: 32945394 PMCID: PMC7473755 DOI: 10.3892/ijo.2020.5103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 05/04/2020] [Indexed: 01/14/2023] Open
Abstract
Lung cancer has the highest incidence and mortality rates among the malignant tumor types worldwide. Platinum‑based chemotherapy is the main treatment for advanced non‑small‑cell lung cancer (NSCLC), and epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) have greatly improved the survival of patients with EGFR‑sensitive mutations. However, there is no standard therapy for treating patients who are EGFR‑TKI resistant. Combining EGFR‑TKIs and platinum‑based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR‑TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR‑TKI) and cisplatin (a main platinum‑based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co‑immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefitinib could selectively inhibit EGFR from entering the nucleus, decrease DNA‑PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA‑dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.
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Affiliation(s)
- Chi Pan
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Huijie Duan
- Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yinan Wu
- Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Chunpeng Zhu
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Chenghao Yi
- Department of Breast Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yin Duan
- Department of Breast Surgery, The Zhejiang Provincial Hospital of Traditional Chinese Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Demin Lu
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Cheng Guo
- Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Deqi Wu
- Department of Gastrointestinal Thyroid and Breast Surgery, The Shulan (Hangzhou) Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yanyan Wang
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Xianhua Fu
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jing Xu
- Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yiding Chen
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Meng Luo
- Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Wei Tian
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Tao Pan
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Wenhong Xu
- Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Suzhan Zhang
- Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jianjin Huang
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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27
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Sun D, Zhu Y, Zhu J, Tao J, Wei X, Wo Y, Hou H. Primary resistance to first-generation EGFR-TKIs induced by MDM2 amplification in NSCLC. Mol Med 2020; 26:66. [PMID: 32611363 PMCID: PMC7329552 DOI: 10.1186/s10020-020-00193-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/22/2020] [Indexed: 12/24/2022] Open
Abstract
Introduction Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20–30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. Methods Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. Results Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. Conclusion MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.
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Affiliation(s)
- Dantong Sun
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong, China
| | - Yan Zhu
- Department of Medical Oncology, The Municipal Hospital of Qingdao, Qingdao, 266000, Shandong, China
| | - Jingjuan Zhu
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong, China
| | - Junyan Tao
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong, China
| | - Xiaojuan Wei
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Yang Wo
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Helei Hou
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong, China.
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First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients. Clin Lung Cancer 2020; 21:e572-e582. [PMID: 32605893 DOI: 10.1016/j.cllc.2020.05.003] [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: 02/04/2020] [Revised: 03/25/2020] [Accepted: 05/06/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND We aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma. PATIENTS AND METHODS Never-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib. RESULTS Between June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR-wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms. CONCLUSIONS Intercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.
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Scodes S, Cappuzzo F. Determining the appropriate treatment for different EGFR mutations in non-small cell lung cancer patients. Expert Rev Respir Med 2020; 14:565-576. [PMID: 32233809 DOI: 10.1080/17476348.2020.1746646] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Epidermal growth factor receptor (EGFR) mutations occur in a significant fraction of non-small cell lung cancer (NSCLC) patients. Most common activating mutations are in-frame deletion in exon 19 and point mutation in exon 21. EGFR tyrosine kinase inhibitors (TKIs) represent standard of care of EGFR mutated patients bearing common mutations. Therapy for individuals carrying uncommon mutations, such as G719X, L861Q, S768I, is less defined and few options exist for individuals harboring EGFR exon 20 mutations. In all mutated patients, drug resistance remains the most critical clinical problem and new agents and strategies are under investigation.Areas covered: We have reviewed the current status of NSCLC EGFR mutated treatment by analyzing data from preclinical studies, clinical prospective and retrospective trials in order to analyze current and future options for patients harboring different EGFR mutations.Expert opinion: At the present time, available data demonstrated that osimertinib is the best EGFR-TKI for front-line therapy. Other agents, such as dacomitinib, and new drug combinations, such as regimens including anti-angiogenic agents or chemotherapy, demonstrated to significantly prolong progression-free survival or overall survival, representing potential alternative to osimertinib. Many questions remain opened, including best drug sequencing and needing of new therapeutic approaches extending patient survival and cure rate.
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Affiliation(s)
- Simona Scodes
- Department of Oncology and Hematology, AUSL Romagna, Ravenna, Italy
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Poursheikhani A, Yousefi H, Tavakoli-Bazzaz J, Seyed H G. EGFR Blockade Reverses Cisplatin Resistance in Human Epithelial Ovarian Cancer Cells. IRANIAN BIOMEDICAL JOURNAL 2020; 24:370-8. [PMID: 32660222 PMCID: PMC7601546 DOI: 10.29252/ibj.24.6.365] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background: EOC is one of the most lethal gynecological malignancy worldwide. Although the majority of EOC patients achieve clinical remission after induction therapy, over 80% relapse and succumb to the chemoresistant disease. Previous investigations have demonstrated the association of EGFR with resistance to cytotoxic chemotherapies, hormone therapy, and radiotherapy in the cancers. These studies have highlighted the role of EGFR as an attractive therapeutic target in cisplatin-resistant EOC cells. Methods: The human ovarian cell lines (SKOV3 and OVCAR3) were cultured according to ATCC recommendations. The MTT assay was used to determine the chemosensitivity of the cell lines in exposure to cisplatin and erlotinib. The qRT-PCR was applied to analyze the mRNA expression of the desired genes. Results: Erlotinib in combination with cisplatin reduced the cell proliferation in the chemoresistant EOC cells in comparison to monotherapy of the drugs (p < 0.05). Moreover, erlotinib/cisplatin combination synergistically decreased the expression of anti-apoptotic and also increased pro-apoptotic genes expression (p < 0.05). Cisplatin alone could increase the expression of MDR genes. The data suggested that EGFR and cisplatin drive chemoresistance in the EOC cells through MEKK signal transduction as well as through EGFR/MEKK pathways in the cells, respectively. Conclusion: Our findings propose that EGFR is an attractive therapeutic target in chemoresistant EOC to be exploited in translational oncology, and erlotinib/cisplatin combination treatment is a potential anti-cancer approach to overcome chemoresistance and inhibit the proliferation of the EOC cells.
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Affiliation(s)
- Arash Poursheikhani
- Medical Genetics Research Centre, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Yousefi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Louisiana State University, School of Medicine, New Orleans, USA
| | - Javad Tavakoli-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghaffari Seyed H
- Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Wróbel-Biedrawa D, Grabowska K, Galanty A, Sobolewska D, Żmudzki P, Podolak I. Anti-melanoma potential of two benzoquinone homologues embelin and rapanone - a comparative in vitro study. Toxicol In Vitro 2020; 65:104826. [PMID: 32169436 DOI: 10.1016/j.tiv.2020.104826] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/29/2020] [Accepted: 03/09/2020] [Indexed: 11/30/2022]
Abstract
Rapanone and embelin are simple alkyl benzoquinone derivatives, mainly distributed in the Primulaceae. They have an interesting scope of biological activities including cytotoxicity. As melanoma is one of the most common types of cancer, in many cases resistant to current treatment regimens, the aim of this study was to assess and compare anti-melanoma activity of the two benzoquinones. Cytotoxicity of both compounds towards different melanoma cell lines (A375, HTB140, WM793) and selectivity with respect to normal keratinocytes (HaCaT) were investigated. Furthermore, interactions with a reference chemotherapeutic, doxorubicine, were assessed. Finally, analysis of anti-inflammatory, antioxidant and anti-tyrosinase activities of both benzoquinones was conducted as well. Rapanone showed selective and higher than doxorubicine cytotoxic potential against primary melanoma cell line, WM793. Although embelin was also highly cytotoxic, its selectivity was much poorer. Interestingly, in case of HTB140 and HaCaT cell lines a combination of each benzoquinone with doxorubicine potentiated the cytotoxic potential in a synergistic manner. Embelin revealed higher albumin anti-denaturation potential than rapanone but lower than diclofenac sodium. Anti-hyaluronidase effect of both benzoquinones was higher than quercetin. Both compounds showed antioxidant potential although significantly lower as compared to vitamin C. Finally, neither embelin nor rapanone had any inhibitory effect on tyrosinase.
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Affiliation(s)
- Dagmara Wróbel-Biedrawa
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Karolina Grabowska
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Agnieszka Galanty
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Danuta Sobolewska
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Paweł Żmudzki
- Department of Medicinal Chemistry, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Irma Podolak
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
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Yang JCH, Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Hozak RR, Nguyen TS, Zhang WL, Enatsu S, Puri T, Orlando M. A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis. J Thorac Oncol 2020; 15:91-100. [DOI: 10.1016/j.jtho.2019.09.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 01/13/2023]
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Kwon JH, Kim KJ, Sung JH, Suh KJ, Lee JY, Kim JW, Kim SH, Lee JO, Kim JW, Kim YJ, Lee KW, Kim JH, Bang SM, Kim S, Yoon SS, Lee JS. Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement. Cells 2019; 8:cells8121538. [PMID: 31795298 PMCID: PMC6953071 DOI: 10.3390/cells8121538] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/21/2019] [Accepted: 11/26/2019] [Indexed: 12/20/2022] Open
Abstract
Background: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. Methods: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. Results: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G1 phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to the parent cell line, whereas A549 and NCI-H460 did not show this change. The pan-HER inhibitor afatinib inhibited this alternative signaling pathway, resulting in a superior cytotoxic effect in pemetrexed-resistant NCI-H3122 cell lines compared to that in the parental cells line. Conclusion: The activation of EGFR-HER2 contributes to the acquisition of resistance to pemetrexed in EML4-ALK rearranged non-small cell lung cancer. However, the inhibition of this alternative survival signaling pathway with RNAi against EGFR-HER2 and with afatinib overcomes this resistance.
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Affiliation(s)
- Ji-Hyun Kwon
- Translational Medicine, Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul 03080, Korea;
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju 28644, Korea
| | - Kui-Jin Kim
- Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam 13620, Korea;
| | - Ji Hea Sung
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Koung Jin Suh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Ji Yun Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Ji-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Se Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Jeong-Ok Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Yu Jung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Soo-Mee Bang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
| | - Soyeon Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea;
| | - Sung-Soo Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea;
| | - Jong Seok Lee
- Translational Medicine, Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul 03080, Korea;
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea; (J.H.S.); (K.J.S.); (J.Y.L.); (J.-W.K.); (S.H.K.); (J.-O.L.); (J.W.K.); (Y.J.K.); (K.-W.L.); (J.H.K.); (S.-M.B.)
- Correspondence: ; Tel.: +82-31-787-7022; Fax: +82-31-787-4052
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Rebuzzi SE, Alfieri R, La Monica S, Minari R, Petronini PG, Tiseo M. Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: Review of the literature and future perspectives. Crit Rev Oncol Hematol 2019; 146:102820. [PMID: 31785991 DOI: 10.1016/j.critrevonc.2019.102820] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/11/2019] [Accepted: 10/13/2019] [Indexed: 12/18/2022] Open
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improved clinical outcome compared to chemotherapy in EGFR mutated advanced non-small cell lung cancer (NSCLC) patients. Nonetheless, acquired resistance develops within 10-14 months and 20-30% of EGFR-mutated patients do not respond to EGFR-TKI. In order to delay or overcome acquired resistance to EGFR-TKIs, combination therapies of EGFR-TKIs with chemotherapy has been investigated with conflicting results. Early studies failed to show a survival benefit because of a lack of patient selection, but more recently clinical studies in EGFR mutated patients have shown promising results. This review summarizes preclinical and clinical studies of combination of EGFR-TKIs, including the third-generation TKI osimertinib, with chemotherapy in first- and second-line settings, using concurrent or intercalated treatment strategies. In the new era of third-generation EGFR-TKIs, new studies of this combination strategy are warranted.
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Affiliation(s)
- Sara Elena Rebuzzi
- Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; Medical Oncology Unit 1, Ospedale Policlinico San Martino IST, University of Genova, Largo Rosanna Benzi 10, 16143, Genova, Italy.
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Silvia La Monica
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Roberta Minari
- Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Pier Giorgio Petronini
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Marcello Tiseo
- Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
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Schneible JD, Singhal A, Lilova RL, Hall CK, Grafmüller A, Menegatti S. Tailoring the Chemical Modification of Chitosan Hydrogels to Fine-Tune the Release of a Synergistic Combination of Chemotherapeutics. Biomacromolecules 2019; 20:3126-3141. [PMID: 31310515 DOI: 10.1021/acs.biomac.9b00707] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Combination chemotherapy with a defined ratio and sequence of drug release is a clinically established and effective route to treat advanced solid tumors. In this context, a growing body of literature demonstrates the potential of hydrogels constructed with chemically modified polysaccharides as depots for controlled release of chemotherapeutics. Identifying the appropriate modification in terms of physicochemical properties of the functional group and its degree of substitution (χ) to achieve the desired release profile for multiple drugs is, however, a complex multivariate problem. To address this issue, we have developed a computational toolbox that models the migration of a drug pair through a hydrated network of polysaccharide chains modified with hydrophobic moieties. In this study, we chose doxorubicin (DOX) and Gemcitabine (GEM) as model drugs, as their synergistic effect against breast cancer has been thoroughly investigated, and chitosan as the model polymer. Our model describes how the modification of chitosan chains with acetyl, butanoyl, and heptanoyl moieties at different values χ governs both the structure of the hydrogel network and drug migration through it. Our experimental data confirm the in silico predictions for both single- and dual-drug release and, most notably, the counterintuitive inversion of release vs χ that occurs when switching from a single- to a dual-drug system. Consensus between predicted and experimental data indicates that acetyl modifications (χ = 32-42%) and butanoyl modifications (χ = 19-24%) provide synergistic GEM/DOX release molar ratios (i.e., 5-10). Collectively, these results demonstrate the potential of this model in guiding the design of chemotherapeutic hydrogels to combat cancer.
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Affiliation(s)
- John D Schneible
- Department of Chemical and Biomolecular Engineering , North Carolina State University , Raleigh , North Carolina 27695 , United States
| | - Ankush Singhal
- Department of Theory and Biosystems , Max Planck Institute for Colloids and Interfaces , Potsdam 14476 , Germany
| | - Radina L Lilova
- Department of Chemical and Biomolecular Engineering , North Carolina State University , Raleigh , North Carolina 27695 , United States
| | - Carol K Hall
- Department of Chemical and Biomolecular Engineering , North Carolina State University , Raleigh , North Carolina 27695 , United States
| | - Andrea Grafmüller
- Department of Theory and Biosystems , Max Planck Institute for Colloids and Interfaces , Potsdam 14476 , Germany
| | - Stefano Menegatti
- Department of Chemical and Biomolecular Engineering , North Carolina State University , Raleigh , North Carolina 27695 , United States
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Kimura T, Kawaguchi T, Chiba Y, Yoshioka H, Watanabe K, Kijima T, Kogure Y, Oguri T, Yoshimura N, Niwa T, Kasai T, Hayashi H, Ono A, Asai K, Tanaka H, Yano S, Yamamoto N, Nakanishi Y, Nakagawa K. Phase I/II study of intermitted erlotinib in combination with docetaxel in patients with recurrent non-small cell lung cancer (WJOG4708L). Jpn J Clin Oncol 2019; 49:947-955. [DOI: 10.1093/jjco/hyz088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/10/2019] [Accepted: 05/24/2019] [Indexed: 11/12/2022] Open
Abstract
Abstract
Background
Preclinical data suggest sequential administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following chemotherapy may improve efficacy. We hypothesized that intermittent delivery of EGFR-TKI following chemotherapy may increase efficacy.
Methods
This was a multicenter, single-arm phase I/II study to evaluate the efficacy of intermitted erlotinib in combination with docetaxel in patients with EGFR-negative NSCLC who failed one prior chemotherapy. The phase I primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of erlotinib. Erlotinib was administered orally once per day on days 2–16 in combination with 60 mg/m2 docetaxel on day1 for 21 days. A standard 3 + 3 dose escalation design was employed for erlotinib from 100 to 150 mg/dose. The phase II primary endpoint was the objective response rate (ORR). The ORR and 95% confidence interval (CI) were calculated using a binomial distribution. This study required 45 patients.
Results
In the phase I part, the planned dose escalation was completed without reaching MTD. The RD of erlotinib was determined as 150 mg/dose. In the phase II part, the ORR and disease control rate were 17.1% (95%CI: 7.2–32.1%) and 53.7% (95%CI: 37.4–69.3%), respectively. Median progression-free survival and overall survival were 3.5 (95%CI: 3.1–4.5) and 11.3 (95%CI: 8.6–16.6) months, respectively. The common non-hematological adverse event was febrile neutropenia (grade 3–4:19.6%). Two treatment-related deaths were occurred because of interstitial lung disease and pleural infection.
Conclusions
Intermittent dosing of erlotinib plus docetaxel is clinically feasible in phase I part but did not significantly improve ORR in phase II part.
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Affiliation(s)
- Tatsuo Kimura
- Graduate School of Medicine, Osaka City University 1-4-3, Asahimachi, Abeno-ku, Osaka-City Osaka, Japan
| | - Tomoya Kawaguchi
- Graduate School of Medicine, Osaka City University 1-4-3, Asahimachi, Abeno-ku, Osaka-City Osaka, Japan
| | - Yasutaka Chiba
- Kinki University Faculty of Medicine 377-2, Ohno-Higashi, Osaka-Sayama-City, Osaka, Japan
| | | | - Katsuya Watanabe
- Yokohama Medical Center 3-60-2 Harajuku, Totsuka-ku, Yokohama-City, Kanagawa, Japan
| | - Takashi Kijima
- Graduate School of Medicine, Osaka University 2-15, Yamadaoka, Suita-City, Osaka, Japan
| | - Yoshihito Kogure
- Nagoya Medical Center 4-1-1 Sannomaru, Naka-ku, Nagoya-City, Aichi, Japan
| | - Tetsuya Oguri
- Nagoya City University 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya-City, Aichi, Japan
| | - Naruo Yoshimura
- Graduate School of Medicine, Osaka City University 1-4-3, Asahimachi, Abeno-ku, Osaka-City Osaka, Japan
| | - Takashi Niwa
- Kurashiki Central Hospital 1-1-1 Miwa, Kurasiki-City Okayama, Japan
| | - Takashi Kasai
- Tochigi Cancer Center 4-9-13 Yonan, Utsunomiya-City, Tochigi, Japan
| | - Hidetoshi Hayashi
- Kinki University Faculty of Medicine 377-2, Ohno-Higashi, Osaka-Sayama-City, Osaka, Japan
| | - Akira Ono
- Shizuoka Cancer Center 1007 Shimonagakubo, Nagaizumi-cho, Sunto-Gun, Shizuoka, Japan
| | - Kazuhisa Asai
- Graduate School of Medicine, Osaka City University 1-4-3, Asahimachi, Abeno-ku, Osaka-City Osaka, Japan
| | - Hiroshi Tanaka
- Niigata Cancer Center Hospital 2-15-3 Kawagishi-Cho, Chuo-Ku, Niigata-City, Niigata, Japan
| | - Seiji Yano
- Kanazawa University 13-1 Takara-machi, Kanazawa-City, Ishikawa, Japan
| | - Nobuyuki Yamamoto
- Wakayama Medical University 811-1 Kimiidera Wakayama-City, Wakayama, Japan
| | - Yoichi Nakanishi
- Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka-City, Fukuoka, Japan
| | - Kazuhiko Nakagawa
- Kinki University Faculty of Medicine 377-2, Ohno-Higashi, Osaka-Sayama-City, Osaka, Japan
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Miller AL, Fehling SC, Garcia PL, Gamblin TL, Council LN, van Waardenburg RCAM, Yang ES, Bradner JE, Yoon KJ. The BET inhibitor JQ1 attenuates double-strand break repair and sensitizes models of pancreatic ductal adenocarcinoma to PARP inhibitors. EBioMedicine 2019; 44:419-430. [PMID: 31126889 PMCID: PMC6604668 DOI: 10.1016/j.ebiom.2019.05.035] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/14/2019] [Accepted: 05/14/2019] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND DNA repair deficiency accumulates DNA damage and sensitizes tumor cells to PARP inhibitors (PARPi). Based on our observation that the BET inhibitor JQ1 increases levels of DNA damage, we evaluated the efficacy of JQ1 + the PARPi olaparib in preclinical models of pancreatic ductal adenocarcinoma (PDAC). We also addressed the mechanism by which JQ1 increased DNA damage. METHODS The effect of JQ1 + olaparib on in vivo tumor growth was assessed with patient-derived xenograft (PDX) models of PDAC. Changes in protein expression were detected by immunohistochemistry and immunoblot. In vitro growth inhibition and mechanistic studies were done using alamarBlue, qRT-PCR, immunoblot, immunofluorescence, ChIP, and shRNA knockdown assays. FINDINGS Tumors exposed in vivo to JQ1 had higher levels of the DNA damage marker γH2AX than tumors exposed to vehicle only. Increases in γH2AX was concomitant with decreased expression of DNA repair proteins Ku80 and RAD51. JQ1 + olaparib inhibited the growth of PDX tumors greater than either drug alone. Mechanistically, ChIP assays demonstrated that JQ1 decreased the association of BRD4 and BRD2 with promoter loci of Ku80 and RAD51, and shRNA data showed that expression of Ku80 and RAD51 was BRD4- and BRD2-dependent in PDAC cell lines. INTERPRETATION The data are consistent with the hypothesis that JQ1 confers a repair deficient phenotype and the consequent accumulation of DNA damage sensitizes PDAC cells to PARPi. Combinations of BET inhibitors with PARPi may provide a novel strategy for treating PDAC. FUND: NIH grants R01CA208272 and R21CA205501; UAB CMB T32 predoctoral training grant.
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Affiliation(s)
- Aubrey L Miller
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL, USA
| | - Samuel C Fehling
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL, USA
| | - Patrick L Garcia
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL, USA
| | - Tracy L Gamblin
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL, USA
| | - Leona N Council
- Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, NP3551 North Pavilion UAB Hospital, Birmingham, AL, USA; The Birmingham Veterans Administration Medical Center, 700 19(th) St S, Birmingham, AL, USA
| | - Robert C A M van Waardenburg
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL, USA
| | - Eddy S Yang
- Department of Radiation Oncology, University of Alabama at Birmingham, Hazelrig Salter Radiation Oncology Center, 1700 6(th) Avenue S, Birmingham, AL, USA
| | - James E Bradner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Karina J Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL, USA.
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La Monica S, Minari R, Cretella D, Flammini L, Fumarola C, Bonelli M, Cavazzoni A, Digiacomo G, Galetti M, Madeddu D, Falco A, Lagrasta CA, Squadrilli A, Barocelli E, Romanel A, Quaini F, Petronini PG, Tiseo M, Alfieri R. Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC. J Exp Clin Cancer Res 2019; 38:222. [PMID: 31138260 PMCID: PMC6537372 DOI: 10.1186/s13046-019-1240-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/21/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive Non-Small Cell Lung Cancer (NSCLC) and more recently for first-line treatment of EGFR-mutant T790M negative NSCLC patients. Similarly to previous generation TKIs, despite the high response rate, disease progression eventually occurs and current clinical research is focused on novel strategies to delay the emergence of osimertinib resistance. In this study we investigated the combination of osimertinib with pemetrexed or cisplatin in EGFR-mutated NSCLC cell lines and xenografts. METHODS Tumor growth was evaluated in a PC9T790M xenograft model and tissue composition was morphometrically determined. PC9, PC9T790M and HCC827 cell lines were employed to test the efficacy of osimertinib and chemotherapy combination in vitro. Cell viability and cell death were evaluated by MTT assay and fluorescence microscopy. Protein expression and gene status were analysed by Western blotting, fluorescence in situ hybridization analysis, next-generation sequencing and digital droplet PCR. RESULTS In xenograft models, osimertinib significantly inhibited tumor growth, however, as expected, in 50% of mice drug-resistance developed. A combination of osimertinib with pemetrexed or cisplatin prevented or at least delayed the onset of resistance. Interestingly, such combinations increased the fraction of fibrotic tissue and exerted a long-lasting activity after stopping therapy. In vitro studies demonstrated the stronger efficacy of the combination over the single treatments in inhibiting cell proliferation and inducing cell death in PC9T790M cells as well as in T790M negative PC9 and HCC827 cell lines, suggesting the potential role of this strategy also as first-line treatment. Finally, we demonstrated that osimertinib resistant clones, either derived from resistant tumors or generated in vitro, were less sensitive to pemetrexed prompting to use a chemotherapy regimen non-containing pemetrexed in patients after progression to osimertinib treatment. CONCLUSIONS Our results identify a combination between osimertinib and pemetrexed or cisplatin potentially useful in the treatment of EGFR-mutated NSCLC patients, which might delay the appearance of osimertinib resistance with long-lasting effects.
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Affiliation(s)
- Silvia La Monica
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Roberta Minari
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Daniele Cretella
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Lisa Flammini
- Food and Drug Department, University of Parma, Parma, Italy
| | - Claudia Fumarola
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Mara Bonelli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Maricla Galetti
- Italian Workers’ Compensation Authority (INAIL) Research Center, Parma, Italy
- Center of Excellence for Toxicological Research (CERT), University of Parma, Parma, Italy
| | - Denise Madeddu
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Angela Falco
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Anna Squadrilli
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Alessandro Romanel
- Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Federico Quaini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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Xu L, Qi Q, Zhang Y, Cui J, Liu R, Li Y. Combination of icotinib and chemotherapy as first-line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: A randomized controlled study. Lung Cancer 2019; 133:23-31. [PMID: 31200823 DOI: 10.1016/j.lungcan.2019.05.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/18/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To explore the efficacy and safety of icotinib with chemotherapy as first-line therapy for advanced lung adenocarcinoma in patients with sensitive epidermal growth factor receptor (EGFR) mutations. METHODS This prospective, randomized, controlled trial was conducted in 10 general hospitals in Shandong Province, China. Previously untreated patients with advanced lung adenocarcinoma and sensitive EGFR mutations were recruited between January 16, 2014 and December 31, 2016 and randomly allocated to the combination group (icotinib plus pemetrexed and carboplatin) or the icotinib only group. The patients were followed up until May 23, 2018. The primary endpoint was progression-free survival (PFS). RESULTS The efficacy analysis (intention-to-treat analysis) include 179 patients (n = 90 in the combination group and n = 89 in the icotinib only group). PFS was significantly longer in the combination group than in the icotinib only group (16.0 months vs. 10.0 months, hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.42-0.84, P = 0.003). The objective response rate and the disease control rate for the combination group were significantly higher than those for the icotinib only group (77.8% vs. 64.0%, χ2 = 4.094, P = 0.043; 91.1% vs. 79.8%, χ2 = 4.632, P = 0.031). However, overall survival did not differ between the two groups (36.0 months vs. 34.0 months, HR = 0.81, 95%CI 0.54-1.22, P = 0.309). The incidence rates of leukopenia and liver function damage of grades 3-4 were higher in the combination group than in the icotinib only group (12.2% vs. 0%, χ2 = 11.086, P = 0.001; 12.2% vs. 3.5%, χ2 = 4.488, P = 0.034). However, adverse events were resolved in most patients. CONCLUSION Use of the combination of icotinib and chemotherapy as first-line therapy significantly improved the PFS of advanced lung adenocarcinoma patients with sensitive EGFR mutations. Although the combination therapy increased the incidence of leukopenia and liver function damage, the observed adverse events were tolerable and manageable.
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Affiliation(s)
- Lisheng Xu
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China
| | - Qian Qi
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China; Department of Respiratory Medicine, Jinan City People's Hospital, No. 001 North Changshao Road, Laiwu District, Jinan, China
| | - Yan Zhang
- Department of Respiratory Medicine, The Fourth People's Hospital of Jinan, No. 050 Shifan Road, Jinan, China
| | - Jiadong Cui
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China; Department of Respiratory Medicine, Dong'e County People's Hospital, No. 275 Shuguang Street, Dong'e County, Liaocheng, China
| | - Ruijuan Liu
- Department of Respiratory Medicine, Jining No.1 People's Hospital, No. 6 Jiankang Road, Jining, China.
| | - Yu Li
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China.
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40
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Liu T, Jin L, Lu W, Gan H, Lin Z, Chen M, Liu J, Zhang F, Wang S, Zhang H, Deng W, Chen H. Sequence-dependent synergistic cytotoxicity of icotinib and pemetrexed in human lung cancer cell lines in vitro and in vivo. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:148. [PMID: 30953548 PMCID: PMC6451286 DOI: 10.1186/s13046-019-1133-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 03/13/2019] [Indexed: 12/17/2022]
Abstract
Background Recent Clinical trials of administration of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with standard first-line chemotherapy have failed to improve survival in patients with advanced NSCLC, However, the sequential treatment with EGFR-TKIs and chemotherapy is expected to improve survival of NSCLC. The aim of this study is to test the antiproliferative effect of pemetrexed combined with icotinib in different sequences on non-small cell lung cancer (NSCLC) cell lines to determine the optimal combination schedule, and subsequently elaborated the potential mechanisms. Methods Six human lung cancer cell lines with wild-type or mutant EGFR gene were exposed to pemetrexed and icotinib combined in different sequences. Cell proliferation was examined by cell counting kit-8 (CCK-8) and colony formation assay; cell cycle and apoptosis were evaluated by flow cytometry; cell migration and invasion were measured by wound healing and transwell invasion assays respectively; protein expression was by detected by Western blot. Results The growth inhibition effect of pemetrexed combined with icotinib on NSCLC cells were schedule-dependent in vitro and in vivo. Treatment with pemetrexed followed by icotinib (P-I) had significantly stronger anticancer ability than treatment with icotinib followed by pemetrexed (I-P) and concomitant treatment with pemetrexed and icotinib (P + I). Cell cycle analysis revealed that pemetrexed blocked cells in S phase, whereas icotinib arrested cells in G1 phase. We also found that icotinib markedly enhanced the pro-apoptotic activity of pemetrexed via cytochrome-C/Caspase/Bcl-2 signaling pathway. In addition, our results showed that pemetrexed alone increased the levels of p-EGFR, p-AKT and p-MAPK, which were inhibited by icotinib. Finally, we showed that the washout period of icotinib was no less than 96 h. Conclusions Sequential treatment of NSCLC cells with pemetrexed followed by icotinib had powerful antiproliferative effect, and it could become a novel effective combination therapy for NSCLC patients.
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Affiliation(s)
- Tianze Liu
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China.,Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Lizi Jin
- Department of Cardiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Wenjing Lu
- Department of Cardiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Hairun Gan
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Zhidong Lin
- Department of General Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China
| | - Miao Chen
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Jiani Liu
- Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Fan Zhang
- Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Siyang Wang
- Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Hongyu Zhang
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China.
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Hongtao Chen
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China.
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Díaz-Serrano A, Gella P, Jiménez E, Zugazagoitia J, Paz-Ares Rodríguez L. Targeting EGFR in Lung Cancer: Current Standards and Developments. Drugs 2019; 78:893-911. [PMID: 29915896 DOI: 10.1007/s40265-018-0916-4] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15-40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile. Up to 50% of patients treated with first- and second-generation TKIs develop an EGFR exon 20 T790M mutation at the time of progression. In this context, osimertinib has shown a great benefit in terms of progression-free survival (PFS) in the second-line setting, including central nervous system metastasis control. The FLAURA trial, which compared osimertinib to first-generation inhibitors as first-line therapy, showed a clear PFS advantage for osimertinib and a trend towards an increased overall survival (OS) assessed by investigator review. Although T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs, other EGFR-dependent and -independent mechanisms have been described, such as HER2 and MET amplifications or BRAF and MEK mutations. Some mechanisms of resistance to osimertinib and other third-generation TKIs have also been described. Several fourth-generation TKIs, targeted drug combinations and immunotherapy strategies are under investigation to overcome resistance to EGFR TKIs in order to improve EGFR-mutant NSCLC patient outcomes.
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Affiliation(s)
- Asunción Díaz-Serrano
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
| | - Pablo Gella
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
| | - Elisabeth Jiménez
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
| | - Jon Zugazagoitia
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
- Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, CT, 06520, USA
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Luis Paz-Ares Rodríguez
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain.
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain.
- Medicine School, Universidad Complutense de Madrid, Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Li Q, Ma W, Li T. Sortilin as a new membrane inhibitor of EGFR trafficking for overcoming resistance to EGFR inhibitors in non-small cell lung cancer. J Thorac Dis 2018; 10:S3186-S3191. [PMID: 30430029 DOI: 10.21037/jtd.2018.08.25] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Qianping Li
- Department of Cardiothoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.,Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Weijie Ma
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Tianhong Li
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.,Veterans Affairs Northern California Health Care System, Mather, CA, USA
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43
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Lim SW, Lee S, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK, Kim ST. Pemetrexed Monotherapy as Salvage Treatment in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy: A Phase II Single-arm Prospective Trial. J Cancer 2018; 9:2910-2915. [PMID: 30123359 PMCID: PMC6096381 DOI: 10.7150/jca.24948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 06/09/2018] [Indexed: 12/12/2022] Open
Abstract
Background: We designed a single-arm, open-label phase II study to determine the efficacy and toxicity of pemetrexed monotherapy with vitamin supplementation in patients with refractory colorectal cancer (CRC) that failed to respond to standard treatments including 5-fluorouracil, oxaliplatin, and irinotecan with or without biologic agents. Methods: Patients were treated with pemetrexed 500 mg/m2 on day 1 every 3 weeks, with folic acid and vitamin B12 supplementation. Treatment was continued until disease progression or intolerable toxicity. Between June 2016 and October 2016, 24 patients were enrolled in this study. Results: One patient withdrew consent, leaving a total of 23 patients for evaluation. The median age of the patients was 54.0 years (range, 23.0 to 67.0), and the median ECOG performance status was 1 (1-2). The median number of previous systemic chemotherapies was 3 (range, 2 to 5). There was no patient with complete response (CR) or partial response (PR). However, stable disease was observed in 10 patients (43.4%) and maintained more than 6 months in 7 of 10 patients. The median progression-free survival was 1.6 months (95% CI, 1.1-2.0) and the median overall survival was 9.8 months (95% CI, 5.9-13.6). Grade 3 treatment-related adverse events occurred in one patient with elevated liver enzymes and hematologic adverse event of grade 2 anemia was observed in one patient. There were no cases of dose reduction or treatment-related deaths and all toxicities were manageable. Conclusions: Pemetrexed monotherapy showed moderate disease control and acceptable toxicity profile as salvage therapy for refractory CRC.
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Affiliation(s)
- Sung Won Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Sujin Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
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44
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Cui J, Zhang Y, Su D, Li T, Li Y. Efficacy of combined icotinib and pemetrexed in EGFR mutant lung adenocarcinoma cell line xenografts. Thorac Cancer 2018; 9:1156-1165. [PMID: 30047610 PMCID: PMC6119608 DOI: 10.1111/1759-7714.12818] [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: 05/03/2018] [Revised: 06/21/2018] [Accepted: 06/21/2018] [Indexed: 12/31/2022] Open
Abstract
Background The combination of EGFR tyrosine kinase inhibitors (TKIs) and chemotherapy is thought to increase treatment efficacy in non‐small‐cell lung cancer (NSCLC). This study investigated the efficacy and potential mechanisms of different combined modes of icotinib plus pemetrexed in EGFR‐mutant lung adenocarcinoma cell line xenograft models. Methods Nude mice were subcutaneously injected with EGFR‐mutant human lung adenocarcinoma cells (HCC827) and randomized into six treatment groups. Tumor xenograft volumes were monitored and recorded. Microvessel density (MVD) and proliferation and apoptosis rates were evaluated with CD34 positive cell counting, and Ki‐67 and caspase‐3 scores, respectively, and determined via immunohistochemistry. Thymidylate synthase (TS), EGFR, and downstream signaling molecule expression was detected by Western blotting. Results The volume and weight of tumor xenografts in the sequential pemetrexed followed by icotinib (Pem‐Ico) group and the concurrent icotinib and pemetrexed (Ico + Pem) group were significantly smaller than those in the control, pemetrexed (Pem), icotinib (Ico), and sequential icotinib followed by pemetrexed (Ico‐Pem) groups. Compared to other groups, a decrease in the MVD and proliferation rate and an increase in the apoptosis rate were observed in the Pem‐Ico and Ico + Pem groups. TS expression and EGFR, AKT, and MAPK phosphorylation were significantly reduced in the Pem‐Ico or Ico + Pem groups. Conclusions Pem‐Ico had additive antitumor activity in vivo, similar to Ico + Pem, both of which are suggested as potentially optimized strategies for treating EGFR‐mutant lung adenocarcinoma.
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Affiliation(s)
- Jiadong Cui
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, China.,Department of Respiratory Medicine, Dong'e County People's Hospital, Liaocheng, China
| | - Yan Zhang
- Department of Respiratory Medicine, Jinan No. 4 People's Hospital, Jinan, China
| | - Di Su
- Department of Respiratory Medicine, Dong'e County People's Hospital, Liaocheng, China
| | - Tao Li
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Yu Li
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, China
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Bisagni A, Pagano M, Maramotti S, Zanelli F, Bonacini M, Tagliavini E, Braglia L, Paci M, Mozzarelli A, Croci S. Higher expression of miR-133b is associated with better efficacy of erlotinib as the second or third line in non-small cell lung cancer patients. PLoS One 2018; 13:e0196350. [PMID: 29689091 PMCID: PMC5916492 DOI: 10.1371/journal.pone.0196350] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 04/11/2018] [Indexed: 12/19/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib, erlotinib and afatinib) are indicated as first-line therapy in patients with non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations in the EGFR gene. Erlotinib is also used in second and third-line therapy for patients whose tumors have wild type EGFR but to date there are no validated biomarkers useful to identify which patients may benefit from this treatment. The expression level of four miRNAs: miR-133b, -146a, -7 and -21 which target EGFR was investigated by real-time PCR in tumor specimens from NSCLC patients treated with erlotinib administered as the second or third line. We found that miR-133b expression level better discriminated responder from non-responder patients to erlotinib. Higher levels of miR-133b in NSCLCs were associated with longer progression-free survival time of patients. Functional analyses on miR-133b through transfection of a miR-133b mimic in A549 and H1299 NSCLC cell lines indicated that increasing miR-133b expression level led to a decreased cell growth and altered morphology but did not affect sensitivity to erlotinib. The detection of miR-133b expression levels in tumors help in the identification of NSCLC patients with a better prognosis and who are likely to benefit from second and third-line therapy with erlotinib.
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Affiliation(s)
- Alessandra Bisagni
- Pathology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
- * E-mail:
| | - Maria Pagano
- Oncology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Sally Maramotti
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Francesca Zanelli
- Oncology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Elena Tagliavini
- Pathology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Luca Braglia
- Scientific Directorate, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Massimiliano Paci
- Thoracic Surgery Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | | | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
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Design, synthesis and anticancer evaluation of novel spirobenzo[h]chromene and spirochromane derivatives with dual EGFR and B-RAF inhibitory activities. Eur J Med Chem 2018; 150:567-578. [DOI: 10.1016/j.ejmech.2018.03.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 02/28/2018] [Accepted: 03/01/2018] [Indexed: 01/16/2023]
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Iwama E, Nakanishi Y, Okamoto I. Combined therapy with epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer. Expert Rev Anticancer Ther 2018; 18:267-276. [PMID: 29363369 DOI: 10.1080/14737140.2018.1432356] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non-small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified. Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations. Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations.
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Affiliation(s)
- Eiji Iwama
- a Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences , Kyushu University , Fukuoka , Japan.,b Research Institute for Diseases of the Chest, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Yoichi Nakanishi
- b Research Institute for Diseases of the Chest, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Isamu Okamoto
- b Research Institute for Diseases of the Chest, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
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Denisenko TV, Budkevich IN, Zhivotovsky B. Cell death-based treatment of lung adenocarcinoma. Cell Death Dis 2018; 9:117. [PMID: 29371589 PMCID: PMC5833343 DOI: 10.1038/s41419-017-0063-y] [Citation(s) in RCA: 515] [Impact Index Per Article: 73.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 08/18/2017] [Accepted: 09/13/2017] [Indexed: 12/13/2022]
Abstract
The most common type of lung cancer is adenocarcinoma (ADC), comprising around 40% of all lung cancer cases. In spite of achievements in understanding the pathogenesis of this disease and the development of new approaches in its treatment, unfortunately, lung ADC is still one of the most aggressive and rapidly fatal tumor types with overall survival less than 5 years. Lung ADC is often diagnosed at advanced stages involving disseminated metastatic tumors. This is particularly important for the successful development of new approaches in cancer therapy. The high resistance of lung ADC to conventional radiotherapies and chemotherapies represents a major challenge for treatment effectiveness. Here we discuss recent advances in understanding the molecular pathways driving tumor progression and related targeted therapies in lung ADCs. In addition, the cell death mechanisms induced by different treatment strategies and their contribution to therapy resistance are analyzed. The focus is on approaches to overcoming drug resistance in order to improve future treatment decisions.
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Affiliation(s)
- Tatiana V Denisenko
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991, Moscow, Russia
| | - Inna N Budkevich
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991, Moscow, Russia
| | - Boris Zhivotovsky
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991, Moscow, Russia. .,Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden.
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Zhang M, Guo H, Zhao S, Wang Y, Yang M, Yu J, Yan Y, Wang Y. Efficacy of epidermal growth factor receptor inhibitors in combination with chemotherapy in advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. Oncotarget 2018; 7:39823-39833. [PMID: 27223081 PMCID: PMC5129973 DOI: 10.18632/oncotarget.9503] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 04/16/2016] [Indexed: 12/18/2022] Open
Abstract
The role of a combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy for non-small-cell lung cancer (NSCLC) has not been well established. To clarify this problem, we performed a meta-analysis with 15 studies identified from PubMed, EMBASE and the Cochrane Library. We found that the combined regimen had a significant benefit on progression-free survival (PFS) (hazard ratio (HR) = 0.80; 95% CI = 0.71–0.90; P < 0.001) and the objective response rate (ORR) (RR = 1.35; 95% CI = 1.14–1.59; P < 0.001). However, the combined regimen had no significant impact on overall survival (OS) (HR = 0.96; 95% CI = 0.90–1.03; P = 0.25). Subgroup analysis showed significantly higher OS advantages in EGFR mutation positive patients (P = 0.01), never smokers (P = 0.01), Asian patients (P = 0.02), patients receiving second-line treatment (P < 0.001), and those receiving a sequential combination of EGFR-TKIs and chemotherapy (P = 0.005). The combination regimen showed a higher incidence of grade 3–4 toxicities (leucopenia, neutropenia, febrile neutropenia, anemia, rash, fatigue and diarrhea). In summary, the combination of EGFR-TKIs plus chemotherapy in advanced NSCLC achieved a significantly longer PFS and a higher ORR but not longer OS. Well-designed prospective studies are needed to confirm these findings.
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Affiliation(s)
- Minghui Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Hongsheng Guo
- Department of Medical Oncology, Tianjin Third Central Hospital, Tianjin, 300170, China
| | - Shu Zhao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yan Wang
- Department of Medical Oncology, Heilongjiang Provincial Hospital, Harbin, 150000, China
| | - Maopeng Yang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiawei Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yubo Yan
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
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Wang S, Gao A, Liu J, Sun Y. First-line therapy for advanced non-small cell lung cancer with activating EGFR mutation: is combined EGFR-TKIs and chemotherapy a better choice? Cancer Chemother Pharmacol 2018; 81:443-453. [PMID: 29327274 DOI: 10.1007/s00280-017-3516-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 12/29/2017] [Indexed: 10/18/2022]
Abstract
As the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the median progression-free survival (PFS) up to 18.9 months. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, which limits the first-line PFS. To overcome the resistance and improve overall survival, researchers have tried to identify the resistance mechanisms and develop new treatment strategies, among which a combination of EGFR-TKIs and cytotoxic chemotherapy is one of the hotspots. The data from preclinical and clinical studies on combined EGFR-TKIs and chemotherapy have shown very interesting results. Here, we reviewed the available preclinical and clinical studies on first-line EGFR-TKIs-chemotherapy combination in patients with advanced NSCLC harboring activating EGFR mutation, aiming to provide evidences for more potential choices and shed light on clinical treatment.
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Affiliation(s)
- Shuyun Wang
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China
| | - Aiqin Gao
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China
| | - Jie Liu
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China.
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