Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review

Abstract

Lung cancer is the leading cause of cancer related deaths in Canada with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Tumor characterization can identify cancer-driving mutations as treatment targets. One of the most successful examples of cancer targeted therapy is inhibition of mutated epidermal growth factor receptor (EGFR), which occurs in ~10-30% of NSCLC patients. While this treatment has benefited many patients with activating EGFR mutations, almost all who initially benefited will eventually acquire resistance. Approximately 50% of cases of acquired resistance (AR) are due to a secondary T790M mutation in exon 20 of the EGFR gene; however, many of the remaining mechanisms of resistance are still unknown. Much work has been done to elucidate the remaining mechanisms of resistance. This review aims to highlight both the mechanisms of resistance that have already been identified in patients and potential novel mechanisms identified in preclinical models which have yet to be validated in the patient settings.

Keywords: Epidermal growth factor receptor (EGFR); antineoplastic; drug resistance; molecular targeted therapy.

Figure 1

Missense mutation is represented by the reference amino acid, followed by the residue number, followed by the mutant residue. For summary of somatic mutations found in EGFR. Mutations in green are typically sensitive to EGFR TKIs, those in red are typically resistant. Approximate frequency of occurrence in NSCLC patients of each mutation is shown in parentheses. *T790M is found in ~5% of pre-EGFR TKI treated patient samples and ~60% of post-EGFR TKI treated patient samples. Horizontal numbers represent exons, vertical numbers represent amino acid residues. X indicates when one amino acid has been shown to be replaced by multiple different amino acids, as example, the glycine at position 719 has been shown to be mutated to an alanine, cysteine, or serine. LREA: string of amino-acids leucine, arginine, glutamate, and alanine). VAIKEL: string of amino-acids valine, alanine, isoleucine, lysine, glutamate, and leucine). TM, transmembrane domain; EGFR, epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors [Modified from Sharma et al. (3)].

Figure 2

Summary of mechanisms of resistance to first generation EGFR TKIs. Reported occurrence of each mechanism varies somewhat cohort to cohort, thus the shown prevalence rates are approximations. Red text represents mutations, blue text represents amplifications. ↑E, increased expression; ↑A, increased activation; ↑R, up-regulation; ↓R, down-regulation; ↓E, loss of expression.