MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer

Abstract

Treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutation with EGFR-TKIs has achieved great success, yet faces the development of acquired resistance as the major obstacle to long-term disease remission in the clinic. MET (or c-MET) gene amplification has long been known as an important resistance mechanism to first- or second-generation EGFR-TKIs in addition to the appearance of T790 M mutation. Recent preclinical and clinical studies have suggested that MET amplification and/or protein hyperactivation is likely to be a key mechanism underlying acquired resistance to third-generation EGFR-TKIs such as osimertinib as well, particularly when used as a first-line therapy. EGFR-mutant NSCLCs that have relapsed from first-generation EGFR-TKI treatment and have MET amplification and/or protein hyperactivation should be insensitive to osimertinib monotherapy. Therefore, combinatorial therapy with osimertinib and a MET or even a MEK inhibitor should be considered for these patients with resistant NSCLC carrying MET amplification and/or protein hyperactivation.

Fig. 1

Chemical structures of third-generation EGFR-TKIs

Fig. 2

MET protein structure (a) and HGF/MET signaling pathway (b). GRB, growth factor receptor-bound protein; SHC, Src homology 2 domain-containing; PI3K, phosphatidylinositol 3-kinase; SOS, son of sevenless; SHP2, Src homology region 2-containing protein tyrosine phosphatase 2; FAK, focal adhesion kinase

Fig. 3

MET amplification causes EGFR-TKI resistance by activating EGFR-independent phosphorylation of ErbB3 and downstream activation of the PI3K/AKT pathway, providing a bypass resistance mechanism in the presence of an EGFR-TKI. MET can also activate PI3K/Akt signaling through ErbB3. In EGFRm NSCLCs with MET amplification, EGFR-TKIs can still inhibit EGFR phosphorylation but not ErbB3 phosphorylation, leading to persistent activation of PI3K/Akt signaling via ErbB3 in an EGFR-independent manner

Fig. 4

Current treatment options for EGFR-mutant NSCLCs and potential strategies for overcoming acquired resistance to osimertinib. The strategies as indicated with dashed lines need clinical validation. METi, MET inhibitor; MEKi, MEK inhibitor

Fig. 5

Chemical structures of small molecule MET inhibitors with their target specificities. IC₅₀, half maximal inhibitory concentration; VEGFR2, vascular endothelial growth factor receptor 2; RET, rearranged during transfection; ALK, anaplastic lymphoma kinase; RON, Recepteur d'Origine Nantais