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

Abstract

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.

• Authors: Helen Y Zou, Qiuhua Li, Joseph H Lee, Maria E Arango, Kristina Burgess, Ming Qiu, Lars D Engstrom, Shinji Yamazaki, Max Parker, Sergei Timofeevski, Jingrong Jean Cui, Michele McTigue, Gerrit Los, Steven L Bender, Tod Smeal, James G Christensen
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 4 Pg. 1036-47 (Apr 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22389468 (Publication Type: Journal Article)
• Copyright: ©2012 AACR.

Chemical References

• 2-(4-(3-quinolin-6-ylmethyl-3H-(1,2,3)triazolo(4,5-b)pyrazin-5-yl)pyrazol-1-yl)ethanol
• Protein Kinase Inhibitors
• Pyrazines
• Triazoles
• RON protein
• Receptor Protein-Tyrosine Kinases

Topics

• 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, metabolism)
• Signal Transduction (drug effects)
• Triazoles (pharmacology)
• Xenograft Model Antitumor Assays