title: Inhibition of tumor growth and metastasis in non-small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET.
abstract: OBJECTIVE
  Lung cancer is the leading cause of cancer-related death worldwide. Sustained activation, overexpression, or mutation of the MET pathway is associated with a poor prognosis in a variety of tumors, including non-small cell lung cancer (NSCLC), implicating the MET pathway as a potential therapeutic target for lung cancer. Previously, we reported on the development of LY2801653: a novel, orally bioavailable oncokinase inhibitor with MET as one of its targets. Here, we discuss the evaluation of LY2801653 in both preclinical in vitro and in vivo NSCLC models. Experimental Design/
  
  
  RESULTS
  Treatment with LY2801653 showed tumor growth inhibition in tumor cell lines and patient-derived tumor xenograft models as a single agent (37.4%-90.0% inhibition) or when used in combination with cisplatin, gemcitabine, or erlotinib (66.5%-86.3% inhibition). Mechanistic studies showed that treatment with LY2801653 inhibited the constitutive activation of MET pathway signaling and resulted in inhibition of NCI-H441 cell proliferation, anchorage-independent growth, migration, and invasion. These in vitro findings were confirmed in the H441 orthotopic model where LY2801653 treatment significantly inhibited both primary tumor growth (87.9% inhibition) and metastasis (64.5% inhibition of lymph node and 67.7% inhibition of chest wall). Tumor-bearing animals treated with LY2801653 had a significantly greater survival time (87% increase compared with the vehicle-treated mice). In the MET-independent NCI-H1299 orthotopic model, treatment with LY2801653 showed a significant inhibition of primary tumor growth but not metastasis.
  
  
  CONCLUSIONS
  Collectively, these results support clinical evaluation of LY2801653 in NSCLCs and suggest that differences in the MET activation of tumors may be predictive of response.
authors.affiliation: Authors' Affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wu
authors.forename: Chen
authors.initials: C
authors.lastname: Bi
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Credille
authors.forename: Jason R
authors.initials: JR
authors.lastname: Manro
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Peek
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Donoho
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.forename: John A
authors.initials: JA
authors.lastname: Wijsman
authors.forename: S Betty
authors.initials: SB
authors.lastname: Yan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Walgren
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C586252:merestinib; D017228:Hepatocyte Growth Factor; D011494:Protein Kinases; D019859:Proto-Oncogene Proteins c-met