Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFRmutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs.Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arisefrom secondary EGFR mutations. Other resistance-inducing processes include mesenchymal–epithelialtransition factor (MET) amplification, epithelial–mesenchymal transformation, phenotypic change fromNSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeuticstrategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking ofmultiple members of the ErbB family. Several molecules which target multiple ErbB receptors are beinginvestigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitiniband lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance(T790M) mutations, are currently under clinical development. Other therapeutic strategies includeinhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 orpoly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodiesagainst the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptorregulation.Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises theimportance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeedcrucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimesin NSCLC.