Sensitivity of Selected Human Tumor Models to PF-04217903, a Novel Selective c-Met Kinase Inhibitor

Helen Y Zou,Max Parker,Jingrong Jean Cui,Steven L Bender,Michele Mctigue,Qiuhua Li,Sergei Timofeevski,Gerrit Los,Ming Qiu,Shinji Yamazaki,Maria E Arango,Tod Smeal,Kristina Burgess,James G Christensen,Lars D Engstrom,Joseph H Lee

doi:10.1158/1535-7163.mct-11-0839

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.

Highlights

An extensive body of literature indicates that c-Met is one of the most frequently genetically altered or otherwise abnormally activated receptor tyrosine kinases (RTK) in various advanced human cancers [1, 2]
PF-04217903 was determined to be greater than 1,000-fold selective for c-Met compared with each of the other kinases included in this collective kinase panel [40]
The antitumor efficacy of PF-04217903 was evaluated in tumor models that (i) harbor MET gene amplification, (ii) exhibit an Hepatocyte growth factor (HGF)/c-Met autocrine loop, or (iii) express high levels of c-Met

Summary

Introduction

An extensive body of literature indicates that c-Met is one of the most frequently genetically altered or otherwise abnormally activated receptor tyrosine kinases (RTK) in various advanced human cancers [1, 2]. Hepatocyte growth factor (HGF), known as scatter factor, is the only known high-affinity ligand of c-Met [4]. C-Met is mainly activated by its ligand, HGF, in a paracrine fashion [4, 5] and is tightly regulated by ligand concentration and activation at the target cell surface and ligand-activated receptor internalization and degradation. Activation of the c-Met pathway provides a powerful signal for cell survival, migration, and proliferation (invasive growth), which is critical during embryonic development and wound healing [6, 7]

Methods

Results

Conclusion