Lung cancer is the most common cause of cancer death globally
Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. improved molecular diagnostics and an increased understanding of the molecular lesions driving lung cancers have facilitated better disease classification and the development of new treatments . Accordingly, NSCLC cases are now classified based on both histology genetic background, which has opened the door to personalized medicine approaches. Recent molecular characterization of patient samples demonstrates that NSCLC arises from alteration of a relatively small subset of genes [4C6], including copy number (CN) gain and exon 14 skipping, which together account for ~6.5% and 3.6% of driver mutations in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cases, respectively [4, 7]. Additional studies have detected CN gain in 2-22% of patients, while others have observed PRT-060318 IC50 MET overexpression in a high percentage of patients . Given the prevalence of MET aberrations across multiple cancer types, it is usually not surprising that MET has been a target of significant clinical interest and drug discovery efforts for several years. Two small-molecule multi-kinase inhibitors with MET inhibitory activity have been FDA approved: cabozantinib and crizotinib. The first of these, cabozantinib, is usually a multi-kinase inhibitor targeting RET, VEGFR2, KIT, TIE2, AXL and the FLT family of kinases in addition to MET  and was FDA-approved in November 2012 for clinical use in progressive metastatic medullary thyroid cancer. A year later, crizotinib, another multi-kinase inhibitor with activity against ALK, RON, ROS1 and MET  was granted FDA approval for ALK-positive metastatic NSCLC. However, the polypharmacology of multi-kinase inhibitors may limit their power due to on- and off-target dose-limiting PRT-060318 IC50 toxicities. Thus, there remains an unmet medical need for potent and highly selective MET inhibitors that may improve upon the ability of cabozantinib and crizotinib to inhibit MET signaling. To this end, more than a dozen clinical candidates, varying in mechanism of action and MET selectivity, have joined clinical trials in the last decade [11C12] ;1) antibodies that hole HGF and block receptor-ligand conversation, 2) antibodies that hole MET and prevent receptor-ligand conversation or receptor dimerization, and 3) small-molecule inhibitors that inhibit MET kinase activity . The MET-binding antibodies ABT-700, LY2875358 and onartuzumab (MetMab) are in Phase I, I/II and I/II/III trials, respectively. Additionally, two HGF-binding antibodiesrilotumumab (AMG102) and ficlatuzumab (AV-299)have joined trials. Rilotumumab reached Phase III trials before safety concerns halted its development in 2014. Several small-molecule MET inhibitors, including savolitinib, INC280, AMG337, LY2801653, SAR125844, MSC2156119J (EMD 1214063), JNJ-38877605 and PHA-665752 have progressed through Phase I and II trials in multiple cancer types; however, JNJ-38877605 trials were terminated due to renal toxicity/lack of a pharmacodynamic response, and development of PHA-665752 was stopped for undisclosed reasons. These clinical candidates have varying mechanisms of action which could result in differences in clinical power. For example, HGF antibodies and the ligand-blocking, monovalent MET antibody onartuzumab may show benefit in ligand-dependent settings, whereas selective small-molecule MET inhibitors may show benefit in both ligand-dependent and ligand-independent settings [14C16]. Recently, the highly-selective and potent small-molecule MET inhibitor savolitinib (volitinib, AZD6094, HMPL-504) has been described , and work by our group and others has exhibited the efficacy of savolitinib in preclinical models of gastric and papillary renal cell cancers [18C19]. While savolitinib is usually currently undergoing Phase I/II clinical testing, the therapeutic potential of savolitinib in lung cancers has not been decided. Here, we demonstrate MET dependency in select NSCLC models by targeting MET with savolitinib. and and CN gain leading to MET dependence can predict MET small-molecule inhibitor sensitivity of tumor cells . In order to select appropriate models for interrogation, we decided savolitinib GI50 values for more than 900 cell lines present in the Sanger Cell Line Panel [21C22], 111 of which represent NSCLC. CN gain in actual LUAD and Ptgfrn LUSC patients, we undertook a bioinformatic analysis of clinical samples from TCGA datasets. We analyzed normal and tumor tissue from 506 LUAD and 501 LUSC patients and found low-level gain (CN >2 but 3) PRT-060318 IC50 in 1.38% and 2.98% of LUAD and LUSC tumors, respectively, while high-level gain (CN >3) was present in 1.97% of LUAD and 1.39% of LUSC samples (Figure ?(Figure1B).1B). We therefore estimate the overall rate of CN gain to be ~3.35% and ~4.37% in LUAD and LUSC patients, respectively. Physique 1 Savolitinib sensitivity in NSCLC cell lines occurs predominately in the other MET inhibitors, we performed a five-day proliferation assay comparing savolitinib to the selective MET inhibitors PHA-665752, JNJ-38877605 and SGX-523 as well as crizotinib, a multi-kinase inhibitor approved for clinical use. Savolitinib was more potent than all other molecules tested, with.