Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Abstract

Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months. Mechanisms determining progression of disease are heterogeneous and not fully understood. EGFR-dependent resistance mechanisms (such as new EGFR mutations), bypass pathway activation [as erb-b2 receptor tyrosine kinase 2 (HER2) or MET amplification] and histological transformation [in small cell lung cancer (SCLC)] have been reported, similarly to previous generation TKIs. Here, we review principle mechanisms of innate and acquired resistance described in literature both in clinical and preclinical settings during NSCLC treatment with third-generation EGFR-TKIs.

Keywords: Epidermal growth factor receptor; T790M; non-small cell lung cancer (NSCLC); resistance; third-generation tyrosine kinase inhibitor.

Figure 1

Mechanisms of resistance to third-generation EGFR TKIs. Schematic representation of innate and acquired resistance described both in clinical and preclinical settings during treatment of non-small cell lung cancer with third-generation epidermal growth factor receptor tyrosine-kinase inhibitors. Mechanisms listed in Italic and with * were observed only in pre-clinical setting. Amp, amplification; del, deletion; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; FGFR1, fibroblast growth factor receptor 1; HER2, erb-b2 receptor tyrosine kinase 2; IGF1R, insulin-like growth factor-1 receptor; EMT, epithelial-mesenchymal transition.