title: 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.affiliation: PGRD-La Jolla, Pfizer, Inc., San Diego, California 92121, USA. helen.zou@pfizer.com
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Li
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arango
authors.forename: Kristina
authors.initials: K
authors.lastname: Burgess
authors.forename: Ming
authors.initials: M
authors.lastname: Qiu
authors.forename: Lars D
authors.initials: LD
authors.lastname: Engstrom
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Max
authors.initials: M
authors.lastname: Parker
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.forename: Jingrong Jean
authors.initials: JJ
authors.lastname: Cui
authors.forename: Michele
authors.initials: M
authors.lastname: McTigue
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Steven L
authors.initials: SL
authors.lastname: Bender
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C558663:2-(4-(3-quinolin-6-ylmethyl-3H-(1,2,3)triazolo(4,5-b)pyrazin-5-yl)pyrazol-1-yl)ethanol; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D014230:Triazoles; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases