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

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

  • Mol Cancer Ther. 2012 Apr;11(4):1036-47. doi: 10.1158/1535-7163.MCT-11-0839.
Helen Y Zou 1 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
Affiliations

Affiliation

  • 1 PGRD-La Jolla, Pfizer, Inc., San Diego, California 92121, USA. helen.zou@pfizer.com
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.

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