Mechanisms of resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors and therapeutic strategies in non-small cell lung cancer

Abstract

Epidermal growth factor receptor (EGFR) T790M mutation is the most frequent mechanism which accounts for about 60% of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. Irreversible EGFR-TKIs which include the second-generation and third-generation EGFR-TKIs are developed to overcome T790M mediated resistance. The second-generation EGFR-TKIs inhibit the wide type (WT) EGFR combined with dose-limiting toxicity which limits its application in clinics, while the development of third-generation EGFR-TKIs brings inspiring efficacy either in vitro or in vivo. The acquired resistance, however, will also occur and limit their response. Understanding the mechanisms of resistance to irreversible EGFR-TKIs plays an important role in the choice of subsequent treatment. In this review, we show the currently known mechanisms of resistance which can be summarized as EGFR dependent and independent mechanisms and potential therapeutic strategies to irreversible EGFR-TKIs.

Keywords: NSCLC; irreversible EGFR-TKIs; mechanisms; resistance; therapeutic strategies.

Figure 1. EGFR-dependent resistance mechanisms of irreversible EGFR-TKIs

EGFR-TKIs compete with ATP for binding to tyrosine kinase domain of EGFR with activating mutations, leading to the inhibition of EGFR and its downstream pathways (MAPK and PI3K/AKT pathways). The secondary or tertiary mutations of EGFR (such as C797S mutation) can change the conformation of tyrosine kinase domain of EGFR, which hinder EGFR-TKIs from binding to EGFR and restore ATP affinity; therefore the downstream pathways are activated leading to the proliferative and anti-apoptotic effect. The activation of downstream signaling is coupled from upstream EGFR activation in EGFR-dependent resistant cells.

Figure 2. EGFR-independent resistance mechanisms of irreversible EGFR-TKIs

EGFR phosphorylation still can be blocked by EGFR-TKIs, but downstream pathways of EGFR remain activated. The activation of other RTKs (c-Met, HER2, IGF1R, FGFR1, etc.) or the aberrant activation of downstream pathways (KRAS gain/mutation, NRAS gain/mutation, BRAF mutation, MAPK1 amplification, PIK3CA mutation, AKT3 activation, PTEN deletion) offer a way bypass EGFR to reactivate of MAPK and PI3K-AKT signaling leading to the proliferative and anti-apoptotic effect. The activation of downstream signaling is uncoupled from upstream EGFR activation in EGFR-independent resistant cells.