Abstract
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.
Highlights
An emerging paradigm in oncology is that robust clinical efficacy can be obtained with inhibitors directed toward oncogenic receptor tyrosine kinases (RTK) that are mutated or otherwiseNote: Supplementary data for this article are available at Cancer Research Online.I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-4443 dysregulated in selected advanced tumors [1, 2]
PF-2341066 potently inhibited the catalytic activity of c-Met and its oncogenic variants in vitro
C-Met–activating mutations have been identified in several human cancers and provide a strong rationale for clinical proof of concept studies
Summary
An emerging paradigm in oncology is that robust clinical efficacy can be obtained with inhibitors directed toward oncogenic receptor tyrosine kinases (RTK) that are mutated or otherwiseNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-4443 dysregulated in selected advanced tumors [1, 2]. In addition to the aforementioned RTKs, c-Met is one of most frequently genetically altered or otherwise dysregulated RTKs in advanced cancers, implicating it as an attractive therapeutic target [4]. Binding of HGF to the c-Met extracellular domain results in receptor multimerization and phosphorylation of multiple tyrosine residues at the intracellular region [5, 6]. Activation of c-Met results in the binding and phosphorylation of adaptor proteins, such as growth factor receptor binding protein 2 (Grb2)–associated binding protein 1 (Gab1), Grb, Src homology and collagen (Shc), and c-Cbl and subsequent activation of signal transducers such as phosphoinositide-3-kinase, Akt, peritoneal lymphocyte-g (PLC-g), signal transducers and activators of transcription (STAT), and extracellular signal-regulated kinases 1 and 2 Activation of c-Met results in the binding and phosphorylation of adaptor proteins, such as growth factor receptor binding protein 2 (Grb2)–associated binding protein 1 (Gab1), Grb, Src homology and collagen (Shc), and c-Cbl and subsequent activation of signal transducers such as phosphoinositide-3-kinase, Akt, peritoneal lymphocyte-g (PLC-g), signal transducers and activators of transcription (STAT), and extracellular signal-regulated kinases 1 and 2 (ERK1 and 2; ref. 10)
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