EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer

T790M mutation is the most common mechanism for resistance to first- and second-generation tyrosine kinase inhibitors (TKI) for epidermal growth factor receptor (EGFR). Several third-generation EGFR mutant selective TKIs are being explored to conquer this resistance. AZD9291 (osimertinib, tagrisso) has been approved for treatment of the metastatic EGFR T790M mutation-positive non-small cell lung cancer. Resistance to AZD9291 has been described. C797S mutation was reported to be a major mechanism for resistance to T790M-targeting EGFR inhibitors. This review summarizes the latest development in identifying the C797S mutation and EAI045, the novel selective inhibitor overcoming the C797S mutant.

• Publication year

  2016

• Venue

  Journal of Hematology & Oncology

• Publication date

  2016-07-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s13045-016-0290-1PMID 27448564PMCID 4957905
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors

  2016influential reference
• Acquired C797S Mutation upon Treatment with a T790M-Specific Third-Generation EGFR Inhibitor (HM61713) in Non-Small Cell Lung Cancer.

  2016cited by this paper
• Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer

  2016cited by this paper
• Highly personalized detection of minimal Ewing sarcoma disease burden from plasma tumor DNA

  2016cited by this paper
• Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer

  2016cited by this paper
• Second- and third-generation ALK inhibitors for non-small cell lung cancer

  2016cited by this paper
• Circulating Biomarkers in Non-Small-Cell Lung Cancer: Current Status and Future Challenges.

  2016cited by this paper
• Comparison of plasma and tissue samples in epidermal growth factor receptor mutation by ARMS in advanced non-small cell lung cancer.

  2016cited by this paper
• Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.

  2016cited by this paper
• Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors

  2016cited by this paper
• The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies

  2015cited by this paper
• Non-invasive approaches to monitor EGFR-TKI treatment in non-small-cell lung cancer

  2015cited by this paper
• First-line nivolumab (anti-PD-1) monotherapy in advanced NSCLC: the story of immune checkpoint inhibitors and "the sorcerers apprentice".

  2015cited by this paper
• Whacking a mole-cule: clinical activity and mechanisms of resistance to third generation EGFR inhibitors in EGFR mutated lung cancers with EGFR-T790M.

  2015cited by this paper
• Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis.

  2015cited by this paper
• Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain.

  2015cited by this paper
• EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients.

  2015cited by this paper
• AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.

  2015cited by this paper
• Advances in the management of gastrointestinal cancers—an upcoming role of immune checkpoint blockade

  2015cited by this paper
• Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M

  2015cited by this paper
• Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.

  2015cited by this paper
• Programmed death 1 blockade, an Achilles heel for MMR-deficient tumors?

  2015cited by this paper
• Novel ALK inhibitors in clinical use and development

  2015cited by this paper
• Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.

  2015cited by this paper
• EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors

  2015cited by this paper
• Rociletinib in EGFR-mutated non-small-cell lung cancer.

  2015cited by this paper
• Near complete response after single dose of nivolumab in patient with advanced heavily pre-treated KRAS mutant pulmonary adenocarcinoma

  2015cited by this paper
• Nivolumab plus ipilimumab in the treatment of advanced melanoma

  2015cited by this paper
• Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI).

  2015cited by this paper
• Functional characterization of BTKC481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors

  2014cited by this paper
• Ceritinib in ALK-rearranged non-small-cell lung cancer.

  2014cited by this paper
• Strategies for modern biomarker and drug development in oncology

  2014cited by this paper
• Novel agents and strategies for overcoming EGFR TKIs resistance

  2014cited by this paper
• AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.

  2014cited by this paper
• Ceritinib in ALK-rearranged non-small-cell lung cancer.

  2014cited by this paper
• BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity

  2014cited by this paper
• Ibrutinib for B cell malignancies

  2014cited by this paper
• Nivolumab as first line monotherapy for advanced non-small cell lung cancer: could we replace first line chemotherapy with immunotherapy?

  2014cited by this paper
• Abstract LB-100: Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor

  2014cited by this paper
• Mechanism for activation of mutated epidermal growth factor receptors in lung cancer

  2013cited by this paper
• Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.

  2013cited by this paper
• Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.

  2013cited by this paper
• Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology

  2013cited by this paper
• Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.

  2013cited by this paper
• The quest to overcome resistance to EGFR-targeted therapies in cancer

  2013cited by this paper
• Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization.

  2013cited by this paper
• Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.

  2013cited by this paper
• Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

  2012cited by this paper
• Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.

  2012cited by this paper
• Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

  2009cited by this paper
• The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor

  2008cited by this paper
• Epidermal growth factor receptor mutations in lung cancer

  2007cited by this paper
• Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.

  2007cited by this paper

• Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation

  2026cites this paper
• New activities of homoyessotoxin against lung cancer through the regulation of EGFR/PI3K/AKT pathway

  2026cites this paper
• Novel Epidermal Growth Factor Receptor (EGFR) Exon20 Insertion-Selective Inhibitors for Lung Cancer Therapy

  2026cites this paper
• A novel MMP-9 inhibitor exhibits selective inhibition in non-small-cell lung cancer harboring EGFR T790M mutation by blocking EGFR/STAT3 signaling pathway.

  2025cites this paper
• Covalent Recruitment of NEDD4 for Targeted Protein Degradation: Rational Design of Small Molecular Degraders.

  2025cites this paper
• Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics

  2025cites this paper
• Design, synthesis and antitumour activity of pyrimidine derivatives as novel selective EGFR kinase inhibitors

  2025cites this paper
• Tissue-based genomic profiling of 300,000 tumors highlights the detection of variants with low allele fraction

  2025cites this paper
• Multidrug Resistance: Are We Still Afraid of the Big Bad Wolf

  2025cites this paper
• 4-O-Demethylbarbatic acid has a novel therapeutic impact on the progression of EGFR-driven lung adenocarcinoma.

  2025cites this paper
• The Future of Cancer Diagnosis and Treatment: Unlocking the Power of Biomarkers and Personalized Molecular-Targeted Therapies

  2025cites this paper
• Precision navigation through the labyrinth: overcoming EGFR resistance in non-Small cell lung cancer

  2025cites this paper
• Circulating tumor cells: indicators of cancer progression, plasticity and utility for therapies

  2025cites this paper
• Effective Degradation of Wild‐Type and Mutant EGFR Using Self‐Assembling Peptide‐Derived PROTAC Nanoparticles (NanoTACs) for Cancer Therapy

  2025cites this paper
• BRG1 (SMARCA4) Status Dictates the Response to EGFR Inhibitors in Wild-Type EGFR Non-Small Cell Lung Cancer

  2025cites this paper
• Osimertinib-Induced Hepatitis Following Immunotherapy in a Patient with Lung Adenocarcinoma Harboring De Novo EGFR Exon 19 Deletion and T790M Mutations: A Case Report

  2025cites this paper
• Amiloride synergizes with EGFR PROTACs and inhibitors to overcome therapeutic resistance in NSCLC.

  2025cites this paper
• EGFR mutations in non-small cell lung cancer: Classification, characteristics and resistance to third-generation EGFR-tyrosine kinase inhibitors (Review)

  2025influential citation
• Anti-MET Antibody Therapies in Non-Small-Cell Lung Cancer: Current Progress and Future Directions

  2024cites this paper
• From challenges to solutions: A review of fourth-generation EGFR tyrosine kinase inhibitors to overcome the C797S triple mutation in non-small cell lung cancer.

  2024cites this paper
• Catalytic Lysine745 targeting strategy in fourth-generation EGFR tyrosine kinase inhibitors to address C797S mutation resistance.

  2024cites this paper
• Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover

  2024cites this paper
• BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer

  2024cites this paper
• Design and investigation of novel iridoid-based peptide conjugates for targeting EGFR and its mutants L858R and T790M/L858R/C797S: an in silico study

  2024cites this paper
• Utility of Circulating Tumor DNA Assay in Identifying Mutations and Guiding Matched Targeted Therapy in Lung Cancers

  2024cites this paper
• Efficacy analysis of immunotherapy‑based combinations for patients with EGFR‑mutant advanced non‑small cell lung cancer after TKI failure

  2024cites this paper
• Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design Strategies.

  2024cites this paper
• Overcoming Cancer Resistance: Strategies and Modalities for Effective Treatment

  2024cites this paper
• Acquired EGFR Resistance Mutation C797S in Pancreatic Adenocarcinoma Following Partial Response to Third-Generation EGFR Inhibitor Therapy.

  2024cites this paper
• A Review of the Molecular Determinants of Therapeutic Response in Non-Small Cell Lung Cancer Brain Metastases

  2024cites this paper
• Promising Combinatorial Therapeutic Strategies against Non-Small Cell Lung Cancer

  2024cites this paper
• Exploring the structural activity relationship of the Osimertinib: A covalent inhibitor of double mutant EGFRL858R/T790M tyrosine kinase for the treatment of Non-Small Cell Lung Cancer (NSCLC).

  2024cites this paper
• BDTX-189, a novel tyrosine kinase inhibitor, inhibits cell activity via ERK and AKT pathways in the EGFR C797S triple mutant cells.

  2024cites this paper
• Parameter estimation from single patient, single time-point sequencing data of recurrent tumors

  2024cites this paper
• EGFR signaling and pharmacology in oncology revealed with innovative BRET-based biosensors

  2024cites this paper
• Small molecule agents for triple negative breast cancer: Current status and future prospects

  2024cites this paper
• Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo

  2023cites this paper
• Uncovering the Structural and Binding Insights of Dual Inhibitors Simultaneously Targeting Two Distinct Sites on EGFR Kinase.

  2023cites this paper
• To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors.

  2023cites this paper
• 4D-QSAR and MIA-QSAR Studies of Aminobenzimidazole Derivatives as Fourth-generation EGFR Inhibitors.

  2023cites this paper
• Revolutionizing Non–Small Cell Lung Cancer Diagnosis: Ultra-High-Sensitive ctDNA Analysis for Detecting Hotspot Mutations with Long-term Stored Plasma

  2023cites this paper
• Mathematical analysis identifies the optimal treatment strategy for epidermal growth factor receptor-mutated non-small cell lung cancer

  2023cites this paper
• Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer

  2023cites this paper
• Efficacy of Osimertinib Continuation plus Metronomic Oral Vinorelbine for EGFR-mutant advanced NSCLC Beyond Limited Progression on Osimertinib.

  2023cites this paper
• The Effects of a Curcumin Derivative and Osimertinib on Fatty Acyl Metabolism and Mitochondrial Functions in HCC827 Cells and Tumors

  2023cites this paper
• Cell-active, irreversible covalent inhibitors that selectively target the catalytic lysine of EGFR by using fluorosulfate-based SuFEx chemistry.

  2023cites this paper
• Successful treatment of severe lung cancer caused by third-generation EGFR-TKI resistance due to EGFR genotype conversion with afatinib plus anlotinib.

  2023cites this paper
• Making the Best Use of Available Weapons for the Inevitable Rivalry-Resistance to EGFR-TKIs

  2023cites this paper
• Comparison between Three Different Techniques for the Detection of EGFR Mutations in Liquid Biopsies of Patients with Advanced Stage Lung Adenocarcinoma

  2023cites this paper
• Histone deacetylase inhibitors as sanguine epitherapeutics against the deadliest lung cancer.

  2023cites this paper
• Multiple post-translational modifications ensure EGFR functionality: Potential therapeutic targets to overcome its drug-resistance mutations.

  2023cites this paper
• Allosteric regulation and inhibition of protein kinases.

  2023cites this paper
• Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation.

  2022cites this paper
• The prospect of combination therapies with the third-generation EGFR-TKIs to overcome the resistance in NSCLC.

  2022cites this paper
• Drug resistance mechanisms and progress in the treatment of EGFR-mutated lung adenocarcinoma

  2022cites this paper
• Proteasomal deubiquitylase activity enhances cell surface recycling of the epidermal growth factor receptor in non-small cell lung cancer

  2022cites this paper
• P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure

  2022cites this paper
• State-of-the-art combination treatment strategies for advanced stage non–small cell lung cancer

  2022cites this paper
• Structural basis for the selectivity of 3rd generation EGFR inhibitors: a molecular dynamics study

  2022influential citation
• The clinical significance and function of EGFR mutation in TKI treatments of NSCLC patients

  2022cites this paper
• A pharmacological exploration of targeted drug therapy in non-small cell lung cancer

  2022cites this paper
• Novel anilinopyrimidine derivatives as potential EGFRT790M/C797S Inhibitors: Design, Synthesis, biological activity study.

  2022cites this paper
• EGFR signaling pathway as therapeutic target in human cancers.

  2022cites this paper
• Hybrid Pharmacophore- and Structure-Based Virtual Screening Pipeline to Identify Novel EGFR Inhibitors That Suppress Non-Small Cell Lung Cancer Cell Growth

  2022cites this paper
• Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm.

  2022cites this paper
• Application of liquid biopsy-based targeted capture sequencing analysis to improve the precision treatment of non-small cell lung cancer by tyrosine kinase inhibitors

  2022cites this paper
• Neurokinin-1 receptor promotes non-small cell lung cancer progression through transactivation of EGFR

  2022cites this paper
• MET inhibitor, capmatinib overcomes osimertinib resistance via suppression of MET/Akt/snail signaling in non-small cell lung cancer and decreased generation of cancer-associated fibroblasts

  2021cites this paper
• Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer.

  2021cites this paper
• Molecular mechanisms of chemo‐ and radiotherapy resistance and the potential implications for cancer treatment

  2021cites this paper
• Noncognate HER2 sensitivity to cognate EGFR allosteric inhibitors at molecular level: New uses for old drugs in gynecological tumors

  2021cites this paper
• Multicellular Effects of STAT3 in Non-small Cell Lung Cancer: Mechanistic Insights and Therapeutic Opportunities

  2021cites this paper
• LS‐106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo

  2021cites this paper
• Contribution of the IdyllaTM System to Improving the Therapeutic Care of Patients with NSCLC through Early Screening of EGFR Mutations

  2021cites this paper
• Visible-Light-Promoted Iron-Catalyzed N-Arylation of Dioxazolones with Arylboronic Acids

  2021cites this paper
• Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma

  2021cites this paper
• A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change

  2021cites this paper
• Defining the Sensitivity Landscape of 74,389 EGFR Variants to Tyrosine Kinase Inhibitors

  2021cites this paper
• Comparison of Resistance Spectra after First and Second Line Osimertinib Treatment Detected by Liquid Biopsy

  2021cites this paper
• De ning the Sensitivity Landscape of 74,389 EGFR Variants to Tyrosine Kinase Inhibitors

  2021cites this paper
• Molecular Mechanisms of Resistance to Osimertinib from Liquid Biopsies of Plasma and Pleura Effusion in EGFR Mutant NSCLC Patients

  2021cites this paper
• Fighting tertiary mutations in EGFR-driven lung-cancers: current advances and future perspectives in medicinal chemistry.

  2021cites this paper
• Identification of genetic variations associated with drug resistance in non-small cell lung cancer patients undergoing systemic treatment

  2021cites this paper
• Iterative Upgrading of Small Molecular Tyrosine Kinase Inhibitors for EGFR Mutation in NSCLC: Necessity and Perspective

  2021cites this paper
• Concurrent use of metformin enhances the efficacy of EGFR-TKIs in patients with advanced EGFR-mutant non-small cell lung cancer—an option for overcoming EGFR-TKI resistance

  2021cites this paper
• Design, synthesis and evaluation of anti-proliferative activity of 2-aryl-4-aminoquinazoline derivatives as EGFR inhibitors.

  2021cites this paper
• Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

  2021cites this paper
• Transformation of NSCLC to SCLC after 1st- and 3rd-generation EGFR-TKI resistance and response to EP regimen and erlotinib

  2021cites this paper
• 6-Color Crystal Digital PCRTM for the High-Plex Detection of EGFR Mutations in Non-Small Cell Lung Cancer.

  2021cites this paper
• Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer.

  2020cites this paper
• Advances in targeting acquired resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors

  2020cites this paper
• Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC).

  2020cites this paper
• Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

  2020cites this paper
• Recent advances in targeted small‐molecule inhibitor therapy for non–small‐cell lung cancer—An update

  2020cites this paper
• Genomic landscape of acquired resistance to third‐generation EGFR tyrosine kinase inhibitors in EGFR T790M‐mutant non–small cell lung cancer

  2020cites this paper
• Mechanistic insights into differential requirement of receptor dimerization for oncogenic activation of mutant EGFR and its clinical perspective

  2020cites this paper
• Advances in covalent kinase inhibitors.

  2020cites this paper
• Potential treatment strategy for the rare osimertinib resistant mutation EGFR L718Q

  2020cites this paper
• A Validated LC Method for the Enantiomeric Separation of EAI045 on Chiral Stationary Phase.

  2020cites this paper
• Salivaomics, Saliva-Exosomics, and Saliva Liquid Biopsy

  2020cites this paper