Mechanisms of resistance to EGFR-targeted drugs: lung cancer

Abstract

Despite the improvement in clinical outcomes derived by the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumours harbour EGFR-activating mutations, prognosis remains unfavourable because of the occurrence of either intrinsic or acquired resistance. We reviewed the published literature and abstracts of oral and poster presentations from international conferences addressing EGFR-TKIs resistance mechanisms discovered in preclinical models and in patients with NSCLC. The molecular heterogeneity of lung cancer has several implications in terms of possible mechanisms of either intrinsic or acquired resistance to EGFR-targeted inhibitors. Several mechanisms of resistance have been described to EGFR-TKIs, such as the occurrence of secondary mutation (T790M, C797S), the activation of alternative signalling (Met, HGF, AXL, Hh, IGF-1R), the aberrance of the downstream pathways (AKT mutations, loss of PTEN), the impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism) and histological transformation. Although some of the mechanisms of resistance have been identified, much additional information is needed to understand and overcome resistance to EGFR-TKI agents. The majority of resistance mechanisms described are the result of a selection of pre-existing clones; thus, studies on the mechanisms by which subclonal alterations have an impact on tumour biology and influence cancer progression are extremely important in order to define the best treatment strategy.

Keywords: EGFR TKIs.

Figure 1

Schematic representation of main EGFR-TKIs resistance mechanisms. Resistance to EGFR-TKIs can occur through different mechanisms either intrinsic or acquired. Known mechanisms are secondary resistance mutations occurring in the ATP-binding domain (such as T790M and C797S), mutation or amplification of bypass signallings (such as AXL, Hh, ERBb2, CRIPTO, etc), activating mutations in the downstream pathways (PI3K, AKT, MEK, RAF), low levels of mRNA or polymorphisms of the pro-apoptotic protein BIM, induction of a transcription programme for EMT and phenotypical changes, or induction of elevated tumour PD-L1 levels. EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; mRNA, messenger RNA; PD-1, programmed death receptor-1; PD-L1, programmed death ligand-1; TKI, tyrosine kinase inhibitor.