Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib > REFERENCE LIBRARY

Receptor tyrosine kinases (RTKs) and their ligand have been found to be genetically altered and overexpressed in various human cancers and therefore considered as therapeutic targets for cancer [1]. The mesenchymal-epithelial transition factor (MET) and its ligand, hepatocyte growth factor, are required for organ regeneration and tissue damage repair, which resemble the pathological process of tumor invasion [2]. Accordingly, aberrant activation of MET signaling cascades including multiple downstream effector pathways such as signal transducer and activator of transcription 3 (STAT3), rat sarcoma (RAS)/mitogen-activated protein kinase (MAPK), and phosphoinositide-3-kinase (PI3K)/AKT, occurs in many types of cancer; receptor crosstalk with other RTKs also has been observed [3]. MET can be inappropriately activated via mutations, amplification and/or overexpression [4-6].

Lung cancer is the leading cause of cancer-related death worldwide. Genetic alteration of MET has been detected in non-small cell lung cancer (NSCLC) and MET amplification has been reported in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-naïve NSCLC patients, with a 

prevalence of 1.4% to 21% [7-10]. In NSCLC, amplification of MET results in constitutive kinase activity in the absence of its ligand; overexpression acts as an oncogenic driver and activator of downstream signaling pathways such as the PI3K/AKT pathway [5,11].

MET presents an attractive therapeutic target for cancers including NSCLC and amplification of MET is an excellent predictive marker of sensitivity to MET-TKIs [6,9,12,13]. Capmatinib (INC280, Novartis) is a highly potent and selective small molecule inhibitor of MET. The selectivity of capmatinib is > 10,000-fold for MET in human kinase assays [14]. In addition, capmatinib demonstrated potent inhibition of cell growth and MET-dependent survival signaling activity in MET-dependent cell lines and patient tumor [6,15]. Although a dramatic response to capmatinib was observed in MET-amplified NSCLC [15], acquired resistance to capmatinib is inevitable. Therefore, in vitro NSCLC cell line models are useful to identify the molecular mechanisms of resistance to capmatinib and establish strategies to overcome it.

In this study, we have established MET-amplified NSCLC cell lines that showed acquired resistance to capmatinib and evaluated its resistance mechanisms. We demonstrated that capmatinib-resistant NSCLC cells were dependent on alternative pathway activation. Despite acquired resistance, the combined inhibition of EGFR or PIK3CA dramatically suppresses cell proliferation and downstream signals of capmatinib-resistant NSCLC cell lines, which suggested that this combination could be an effective therapeutic strategy against MET-TKI resistance in NSCLC patients.