Abstract A40: A novel cMET pharmacodynamic assay using human hair follicles.

The Receptor Tyrosine Kinase cMET is an oncogenic driver of gastric and lung cancer. Clinical development of cMET inhibitors to treat these cancers would be aided by a robust Pharmacodynamic (PD) marker, as we have observed heterogenous expression of phosphor-cMET (pMET) in these tumor types with limited clinical access. Here we describe the development of a novel cMET PD marker in plucked human hair follicles to address these issues. To evaluate the presence of activated cMET this surrogate tissue, 50 ug of protein extract derived from 25 plucked human hair follicles was analyzed by Receptor Tyrosine Kinase arrays. Active EGFR, HER2, HER3 IGF1R, Insulin receptor, EphA1, EphB2, and ROR1 were observed; however, no active MET was detected. Ex vivo treatment of human hair follicles with the cMET ligand HGF did however induce activation of MET as measured by pMET. A quantitative METpY1349 mesoscale assay demonstrated that HGF activated MET could be detected in a little as 2 human hair follicles or 1 ug of protein. HGF (EC50 22 ng/ml) induced a 22–38 fold time-dependent increase in pMETpY1349 and could be inhibited by the selective cMET inhibitor MK-2461 (IC50 63 nM). Current efforts to translate this assay to preclinical species will be described. These data provide additional evidence for the expression of functional cMET in human hair follicles and assays described may provide alternative means for measuring cMET inhibitor effect in a clinically relevant surrogate tissue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A40.