Mechanisms of Resistance to EGFR TKIs and Development of a New Generation of Drugs in Non‐Small‐Cell Lung Cancer

Abstract

Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

“…Previous studies have demonstrated the benefits of afatinib on patient OS using pooled data from the LUX-lung 3 and 6 clinical trials (11,12,18). Afatinib is hypothetically more effective at inhibiting EGFR signaling than reversible TKIs, due it forming stable covalent bonds and irreversibly inhibiting ATP from binding to the tyrosine kinase domain of EGFR (19); however, no randomized clinical trial or meta-analysis has demonstrated that afatinib is superior to erlotinib or gefitinib regarding OS. Irreversible TKIs have been reported to significantly improve the OS time of patients with exon 19 deletions (20,21).…”

Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation

“…These agents effectively inhibit EGFR activity by irreversible binding to EGFR. Afatinib (BIBW2992) and dacomitinib (PF299804) are representative second-generation irreversible EGFR TKIs currently undergoing clinical trial and have shown promising antitumor activity in NSCLC (6,7). Because these agents have been reported to exhibit antitumor activity in preclinical studies using NSCLC cells harboring the EGFR T790M, they are expected to be standard therapeutic options for patients with EGFR T790M (7)(8)(9).…”

HGFK1 is Associated with a Better Prognostis and Reverses Inhibition by Gefitinib in NSCLC Cases

“…A small molecule Met inhibitor combined with an EGFR TKI has proven to be a reasonable strategy to overcome erlotinib-resistant T790M NSCLC (Li et al, 2008). Combining an insulin-like growth factor inhibitor with erlotinib to reverse resistance to erlotinib is also under investigation (Tang et al, 2008;Kosaka et al, 2011). However, most of these treatments are not clinically available.…”