Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors

Abstract

Patients with non-small-cell lung cancer (NSCLC) whose tumours harbour activating mutations within the epidermal growth factor receptor (EGFR) frequently derive significant clinical and radiographic benefits from treatment with EGFR tyrosine kinase inhibitors (TKIs). As such, prospective identification of EGFR mutations is now the standard of care worldwide. However, acquired therapeutic resistance to these agents invariably develops. Over the past 10 years, great strides have been made in defining the molecular mechanisms of EGFR TKI resistance in an effort to design rational strategies to overcome this acquired drug resistance. Approximately 60% of patients with acquired resistance to the EGFR TKIs (erlotinib, gefitinib, and afatinib) develop a new mutation within the drug target. This mutation-T790M-has been shown to alter drug binding and enzymatic activity of the mutant EGF receptor. Less common mechanisms of acquired resistance include MET amplification, ERBB2 amplification, transformation to small-cell lung cancer, and others. Here, we present a condensed overview of the literature on EGFR-mutant NSCLC, paying particular attention to mechanisms of drug resistance, recent clinical trial results, and novel strategies for identifying and confronting drug resistance, while also striving to identify gaps in current knowledge. These advances are rapidly altering the treatment landscape for EGFR-mutant NSCLC, expanding the armamentarium of available therapies to maximize patient benefit.

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

“…Among the 109 EGFR-TKI refractory cases in our cohort, approximately half had EGFR T790M (n = 54), while 20 additional patients (18%) showed other genetic alterations associated with TKI resistance, including rare EGFR mutations (n = 4), PIK3CA mutations (n = 4), CTNNB1 mutations (n = 3), MET mutations (n = 2) or amplification (n = 1), PDGFRA mutations (n = 2), immunhistochemically proven SCLC transformation (with TP53 mutations, n = 2), and KRAS mutation (n = 1). 59,60 In summary, our work demonstrates the feasibility and significant advantages of comprehensive, DNA-and RNA-based targeted NGS profiling of NSCLC in a routine clinical setting by presenting the largest single-institution cohort reported to date. Most of these secondary alterations prevent binding or bypass the effect of EGFR and ALK inhibitors by triggering receptor-independent downstream signaling.…”

“…In the remaining resistant EGFR + and ALK + cases, disease progression was presumably due to complex mechanisms not detectable in our panel-based sequencing approach and not amenable to further TKI treatment. 59,60 In summary, our work demonstrates the feasibility and significant advantages of comprehensive, DNA-and RNA-based targeted NGS profiling of NSCLC in a routine clinical setting by presenting the largest single-institution cohort reported to date. Our results expand the prevalence of main targetable mutations reported from compiled cohorts, such as the TCGA, and highlight the additional prognostic and predictive insights gained by the simultaneous considering of cooccuring genetic alterations.…”

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non–Small Cell Lung Cancer

“…Molecular mechanisms of acquired resistance to EGFR-TKIs involve drug target alterations (e.g., EGFR T790M mutation) or bypass signaling activations (e.g., MET amplification, ERBB2 amplification). The gatekeeper T790M mutation in EGFR kinase is the most common (approximately 60%) resistance mechanism following firstand second-generation EGFR-TKI treatment (6,7). Therefore, efforts have been made to target the EGFR T790M mutation, resulting in the development of third-generation EGFR-TKIs, including rociletinib (CO-1686), olmutinib (HM61713), and osimertinib (AZD9291; refs.…”

Inhibition of NF‐κB improves sensitivity to irradiation and EGFR‐TKIs and decreases irradiation‐induced lung toxicity

“…31,32 However, their effectiveness is limited by the development of radioresistance and the inevitable occurrence of EGFR-TKI resistance. 33,34 They are also limited due to radiation-induced lung injury and TKI-induced interstitial lung disease. 35,36 In our study, we demonstrated that irradiation-induced NF-κB activation plays a vital role in resistance to radiotherapy and EGFR-TKIs in NSCLC.…”