Sensitivity of selected human tumor models to PF-04217903, a novel selective c-Met kinase inhibitor

• Published in: Molecular cancer therapeutics Vol. 11; no. 4; pp. 1036 - 1047
• Main Authors: Zou, Helen Y, Li, Qiuhua, Lee, Joseph H, Arango, Maria E, Burgess, Kristina, Qiu, Ming, Engstrom, Lars D, Yamazaki, Shinji, Parker, Max, Timofeevski, Sergei, Cui, Jingrong Jean, McTigue, Michele, Los, Gerrit, Bender, Steven L, Smeal, Tod, Christensen, James G
• Format: Journal Article
• Language: English
• Published: United States 01-04-2012
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Humans; Mice; Mice, Nude; Protein Kinase Inhibitors - pharmacology; Pyrazines - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Signal Transduction - drug effects; Triazoles - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-11-0839

The c-Met pathway has been implicated in a variety of human cancers for its critical role in tumor growth, invasion, and metastasis. PF-04217903 is a novel ATP-competitive small-molecule inhibitor of c-Met kinase. PF-04217903 showed more than 1,000-fold selectivity for c-Met compared with more than 150 kinases, making it one of the most selective c-Met inhibitors described to date. PF-04217903 inhibited tumor cell proliferation, survival, migration/invasion in MET-amplified cell lines in vitro, and showed marked antitumor activity in tumor models harboring either MET gene amplification or a hepatocyte growth factor (HGF)/c-Met autocrine loop at well-tolerated dose levels in vivo. Antitumor efficacy of PF-04217903 was dose-dependent and showed a strong correlation with inhibition of c-Met phosphorylation, downstream signaling, and tumor cell proliferation/survival. In human xenograft models that express relatively high levels of c-Met, complete inhibition of c-Met activity by PF-04217903 only led to partial tumor growth inhibition (38%-46%) in vivo. The combination of PF-04217903 with Recepteur d'origine nantais (RON) short hairpin RNA (shRNA) knockdown in the HT29 model that also expresses activated RON kinase-induced tumor cell apoptosis and resulted in enhanced antitumor efficacy (77%) compared with either PF-04217903 (38%) or RON shRNA alone (56%). PF-04217903 also showed potent antiangiogenic properties in vitro and in vivo. Furthermore, PF-04217903 strongly induced phospho-PDGFRβ (platelet-derived growth factor receptor) levels in U87MG xenograft tumors, indicating a possible oncogene switching mechanism in tumor cell signaling as a potential resistance mechanism that might compromise tumor responses to c-Met inhibitors. Collectively, these results show the use of highly selective inhibition of c-Met and provide insight toward targeting tumors exhibiting different mechanisms of c-Met dysregulation.