Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non–Small-Cell Lung Cancer

Abstract

The MET inhibitor INC-280 restored sensitivity to erlotinib and promoted apoptosis in non–small-cell lung cancer models rendered resistant to erlotinib by hepatocyte growth factor. Background Although the epidermal growth factor receptor (EGFR) inhibitor erlotinib is initially effective in non–small-cell lung cancer (NSCLC) patients with tumors harboring activating mutations of EGFR, most subsequently develop acquired resistance. One recognized resistance mechanism occurs through activation of bypass signaling via the hepatocyte growth factor (HGF)-MET pathway. INC-280 is a small molecule kinase inhibitor of MET. We sought to demonstrate the activity of INC-280 on select NSCLC cell lines both as a single agent and in combination with erlotinib using exogenous HGF to simulate MET up-regulation. Methods Four NSCLC cell lines (HCC827, PC9, H1666, and H358) were treated with either single-agent INC-280 or in combination with erlotinib with or without HGF. The activity of the drug treatments was measured by cell viability assays. Immunoblotting was used to monitor expression of EGFR/pEGFR, MET/pMET, GAB1/pGAB1, AKT/pAKT, and ERK/pERK as well as markers of apoptosis (PARP and capase-3 cleavage) in H1666, HCC827, and PC9. Results As a single agent, INC-280 showed minimal cytotoxicity despite potent inhibition of MET kinase activity at concentrations as low as 10 nM. Addition of HGF prevented erlotinib-induced cell death. The addition of INC280 to HGF-mediated erlotinib-resistant models restored erlotinib sensitivity for all cell lines tested, associated with cleavage of both PARP and caspase-3. In these models, INC-280 treatment was sufficient to restore erlotinib-induced inhibition of MET, GAB1, AKT, and ERK in the presence of HGF. Conclusion Although the MET inhibitor INC-280 alone had no discernible effect on cell growth, it was able to restore sensitivity to erlotinib and promote apoptosis in NSCLC models rendered erlotinib resistant by HGF. These data provide a preclinical rationale for an ongoing phase 1 clinical trial of erlotinib plus INC-280 in EGFR-mutated NSCLC.

Emerging therapies for non-small cell lung cancer

“…MET amplification could be accounted for 5-26% in patients resistant to previous EGFR-TKI [20,[155][156][157][158][159]. Preclinical research suggested INC280 could restore sensitivity to erlotinib and promote apoptosis in EGFR-mutant NSCLC models [160]. As a clinical rationale for the combination of capmatinib and EGFR-TKI, a phase Ib/II single-arm trial evaluated the combination of INC280 and gefitinib in EGFR-TKI-pretreated patients [161].…”

Development and full validation of an LC–MS/MS methodology to quantify capmatinib (INC280) following intragastric administration to rats

“…It is a member of a distinct subfamily of heterodimeric receptor tyrosine kinases and encodes the high‐affinity receptor for hepatocyte growth factor (Baltschukat et al, ; Shaker, Ashamallah, & El‐Mesery, ). Dysregulation of MET signaling results in activation of downstream pathways, including the RAS/MAPK, PI3K/AkT and Rac/Rho pathways, which promote cell proliferation, survival and metastasis (Kim et al, ; Lara et al, ). Aberrant activation of the MET pathway may be a result of high‐level MET gene amplification, protein overexpression or gene mutations, and is associated with resistance to chemotherapy and radiotherapy and poor clinical outcomes in cancer patients (Burki, ; Esaki et al, ; Ko & Halmos, ).…”

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

“…In many cases, it has been shown that newer strategies, such as combinatorial treatment,8,218 yield very effective results. For instance, combined treatment with EGFR and MET inhibitors significantly inhibits the activation of EGFR downstream components, reducing the growth, proliferation, and survival of tumor cells 219,220. Platinum-based chemotherapeutics such as cisplatin and carboplatin, are frequently used to treat many types of cancer, including lung cancer.…”