Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations

Abstract

Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10-16 months, followed by disease progression. Moreover, ~20%-30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance.

Keywords: EGFR TKIs; EGFR mutation; NSCLC; T790M; intrinsic resistance.

Figure 1

Major molecular mechanisms of intrinsic resistance to EGFR TKIs in tumors harboring activating EGFR mutations. Notes: EGFR T790M mutations, EGFR exon 20 insertions, HGF overexpression, HER2 exon 20 insertions, IGF-1R activation by binding to IGF-1, PTEN loss, PI3KCA mutations, BIM deletions, or alteration of its mRNA contribute to inhibition of cell proliferation and survival or suppression of apoptosis, which ultimately results in intrinsic resistance to EGFR TKIs in EGFR-mutant patients receiving EGFR TKI therapy. Abbreviation: TKIs, tyrosine kinase inhibitors.