ArticleNeoplasia (New York, N.Y.)2019
Overcoming Resistance to AC0010, a Third Generation of EGFR Inhibitor, by Targeting c-MET and BCL-2.
Article in Neoplasia (New York, N.Y.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- A Novel Third-generation EGFR Tyrosine Kinase Inhibitor Abivertinib for EGFR T790M-mutant Non-Small Cell Lung Cancer: a Multicenter Phase I/II Study.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Trial
- Review
- Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.Signal transduction and targeted therapy · 2023Review
- Preclinical Models for Acquired Resistance to Third-Generation EGFR Inhibitors in NSCLC: Functional Studies and Drug Combinations Used to Overcome Resistance.Frontiers in oncology · 2022Review
- Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies.Medical oncology (Northwood, London, England) · 2021Review
- Novel Bis- and Mono-Pyrrolo[2,3-Molecules (Basel, Switzerland) · 2021Article
- Has programmed cell death ligand-1Translational lung cancer research · 2021Review
- Synergistic effects of Bcl-2 inhibitors with AZD9291 on overcoming the acquired resistance of AZD9291 in H1975 cells.Archives of toxicology · 2020Article
- Canadian consensus: a new systemic treatment algorithm for advancedCurrent oncology (Toronto, Ont.) · 2020Article
- Frontiers of ctDNA, targeted therapies, and immunotherapy in non-small-cell lung cancer.Translational lung cancer research · 2020Review
- Exosome-Delivered c-Met siRNA Could Reverse Chemoresistance to Cisplatin in Gastric Cancer.International journal of nanomedicine · 2020Article
- MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.Journal of hematology & oncology · 2019Review
- Impact of MET alterations on targeted therapy with EGFR-tyrosine kinase inhibitors for EGFR-mutant lung cancer.Biomarker research · 2019Review
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
AC0010 is a pyrrolopyrimidine-based irreversible inhibitor of epidermal growth factor receptor (EGFR), structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR T790M mutation in both preclinical and clinical studies. However, AC0010 treatment eventually triggers drug resistance with unknown mechanism. To this end, we established two H1975 NSCLC-derived lines resistant to AC0010 after a series of drug exposure and selection in either nude-mice xenograft tumor (H1975-P) or cell culture (H1975-AVR) settings. Both lines obtained 100-fold resistance to AC0010 as compared to the parental lines. To elucidate underlying mechanism, we performed unbiased RNAseq-based profiling analysis and found that H1975-P cells had c-MET overexpression, whereas H1975-AVR cells had BCL-2 overexpression. AC0010 resistance was partially abrogated by targeting c-MET or BCL-2 using either pharmacological (small molecule inhibitors) and/or genetic (siRNA-based knockdown) approach, respectively. Our study shows that drug resistance to AC0010 can be developed via the different mechanism in a cell context-dependent manner and provides the proof-of-concept evidence for rational drug combinations to overcome resistance for maximal therapeutic efficacy.
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