Abstract
Hepatocyte growth factor (HGF) is the ligand for the tyrosine kinase receptor c-Met (Mesenchymal Epithelial Transition Factor also known as Hepatocyte Growth Factor Receptor, HGFR), a receptor with expression throughout epithelial and endothelial cell types. Activation of c-Met enhances cell proliferation, invasion, survival, angiogenesis, and motility. The c-Met pathway also stimulates tissue repair in normal cells. A body of past research shows that increased levels of HGF and/or overexpression of c-Met are associated with poor prognosis in several solid tumors, including lung cancer, as well as cancers of the head and neck, gastro-intestinal tract, breast, ovary and cervix. The HGF/c-Met signaling network is complex; both ligand-dependent and ligand-independent signaling occur. This article will provide an update on signaling through the HGF/c-Met axis, the mechanism of action of HGF/c-Met inhibitors, the lung cancer patient populations most likely to benefit, and possible mechanisms of resistance to these inhibitors. Although c-Met as a target in non-small cell lung cancer (NSCLC) showed promise based on preclinical data, clinical responses in NSCLC patients have been disappointing in the absence of MET mutation or MET gene amplification. New therapeutics that selectively target c-Met or HGF, or that target c-Met and a wider spectrum of interacting tyrosine kinases, will be discussed.
Highlights
The c-Met oncogene was first isolated from a human osteosarcoma cell line, which contained a DNA rearrangement: the translocated promoter region (TPR) locus on chromosome 1 was fused to the MET gene on chromosome 7 [1]
Many non-small cell lung cancer (NSCLC) patients eventually became resistant to alectinib and one common mechanism of acquired resistance to anaplastic lymphoma kinase (ALK) TKIs is the secretion of Hepatocyte growth factor (HGF) into the tumor microenvironment, leading to HGF-dependent c-Met signaling [89]
The c-Met pathway is frequently overactive in NSCLC, inhibiting either the c-Met receptor itself or its ligand HGF has not proven effective as single therapy in unselected NSCLC
Summary
All subjects start cabozantinib at 40 mg. Those who tolerate 40 mg for 2 cycles will escalate to 60 mg NCT02101736. Escalating doses (50–740 mg/m2 ) given IV weekly for 6 weeks or until progression. Drug was well tolerated and anti-tumor activity was observed only in MET amplified patients [33]. Dose escalation of IV emibetuzumab, in combination with a fixed dose of IV ramucirumab on days 1 and 15 of every 28 day cycle. Multi-kinase ATP-competitive inhibitor of c-Met and VEGFRs plus Erlotinib (EGFR TKI). Dose-related activity seen in patients with no prior EGFR TKI treatment, some in EGFR WT patients [35]. Cycle 1: single dose at 2x the dose assignment; Cycle 2 and beyond: dose once every two weeks.
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