{"doi":"10.1016/j.cllc.2016.11.006","title":"Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non–Small-Cell Lung Cancer","abstract":null,"journal":"Clinical Lung Cancer","year":2017,"id":657330,"datarank":2.4268669801878726,"base_score":3.6888794541139363,"endowment":3.6888794541139363,"self_citation_contribution":0.5533319181170905,"citation_network_contribution":1.8735350620707822,"self_endowment_contribution":0.5533319181170905,"citer_contribution":1.8735350620707822,"corpus_percentile":null,"corpus_rank":null,"citation_count":39,"citer_count":38,"citers_with_citation_signal":34,"citers_with_endowment":34,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1715950,"name":"William S. Holland","orcid":null,"position":1,"is_corresponding":false},{"id":1715952,"name":"Danielle Chinn","orcid":null,"position":2,"is_corresponding":false},{"id":1715955,"name":"Rebekah A. Burich","orcid":null,"position":3,"is_corresponding":false},{"id":263635,"name":"Primo N. Lara","orcid":"0000-0001-9512-0002","position":4,"is_corresponding":false},{"id":268633,"name":"David R. Gandara","orcid":"0000-0003-1784-048X","position":5,"is_corresponding":false},{"id":268632,"name":"Karen Kelly","orcid":"0000-0002-2235-6636","position":6,"is_corresponding":false},{"id":268623,"name":"Philip C. Mack","orcid":"0000-0003-4750-3812","position":7,"is_corresponding":false},{"id":1239880,"name":"Matthew S. Lara","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non–Small-Cell Lung Cancer","abstract":"<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.","is_dataset_classified":null,"base_score":3.6888794541139363,"endowment":3.6888794541139363,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28038979","pmcid":"PMC5837026","openalex_id":"https://openalex.org/W2551486460","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P30 CA093373","title":null}],"total_grants":1,"fwci":2.1693,"citation_percentile":0.88352996,"influential_citations":0,"citation_trend":[{"year":2017,"count":2},{"year":2018,"count":3},{"year":2019,"count":8},{"year":2020,"count":7},{"year":2021,"count":10},{"year":2022,"count":2},{"year":2023,"count":3},{"year":2024,"count":1},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"closed","license":"https://www.elsevier.com/legal/tdmrep-license","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S1525730416303606?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S1525730416303606?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.cllc.2016.11.006","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28038979","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5837026","host_type":"repository"},{"url":"https://escholarship.org/uc/item/65980945","host_type":"repository"}],"fields_of_study":["Liver physiology and pathology","Lung Cancer Treatments and Mutations","Fibroblast Growth Factor Research","Antineoplastic Combined Chemotherapy Protocols","Apoptosis","Benzamides","Carcinoma, Non-Small-Cell Lung","Caspase 3","Cell Line, Tumor","Cell Proliferation","Drug Evaluation, Preclinical","Drug Resistance, Neoplasm","ErbB Receptors","Erlotinib Hydrochloride","Humans","Imidazoles","Lung Neoplasms","Poly(ADP-ribose) Polymerases","Proto-Oncogene Proteins c-met","Triazines"],"mesh_terms":["Erlotinib Hydrochloride","Antineoplastic Combined Chemotherapy Protocols","Benzamides","Carcinoma, Non-Small-Cell Lung","Drug Evaluation, Preclinical","Humans","Imidazoles","Lung Neoplasms","Poly(ADP-ribose) Polymerases","Triazines","Apoptosis","Drug Resistance, Neoplasm","Proto-Oncogene Proteins c-met","Cell Line, Tumor","Cell Proliferation","Caspase 3","ErbB Receptors"],"keywords":["Erlotinib","Epidermal growth factor receptor","EGFR inhibitors","Hepatocyte growth factor","Medicine","Cancer research","Erlotinib Hydrochloride","Protein kinase B","Lung cancer","Pharmacology","Epidermal growth factor","MAPK/ERK pathway","Apoptosis","Kinase","Cancer","Chemistry","Internal medicine","Receptor","Biochemistry","ERK","Combination therapy","AKT","acquired resistance","Egfr Mutant"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T00:41:06.682048Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}