Abstract 1821: Hepatocyte growth factor sensitizes brain tumor cells and xenografts to c-Met kinase inhibition
Authors: Zhang Ying , Farenholtz Kaithlyn , Yang Yanzhi , Guessous Fadila , Schiff David , Purow Benjamin , Christensen James , Abounader Roger 
Published: August 2012

The receptor tyrosine kinase c-Met and its ligand hepatocyte growth factor (HGF) are frequently deregulated in many cancers, including brain tumors. c-Met activation induces brain tumor malignancy and is associated with poor clinical outcome. Consequently, c-Met inhibitors have been developed by pharmaceutical companies. However, the factors that determine sensitivity to c-Met inhibitors have not been determined to date. In the present study, we systematically investigated the factor(s) that determine sensitivity of brain tumors to c-Met kinase inhibitors and thereby also uncovered a new strategy for enhancing sensitivity to the inhibitors. We investigated the effects of a clinically applicable c-Met kinase inhibitor, PF-2341066, on fifteen different medulloblastoma and glioma cells and stem cells that possess different molecular characteristics. We investigated potential correlations between the effects of PF-2341066 on cell proliferation and death and the levels of total c-Met, p-Met, HGF, PTEN and EGFR co-expression. PF-2341066 completely inhibited basal and HGF-induced c-Met activation in all cells. However, the effects of PF-2341066 on cell proliferation and cell death varied tremendously between the different cell lines. The anti-proliferative and anti-survival effects of PF-2341066 did not correlate with c-Met, phospho-Met or PTEN or EGFR expressions in the cells. However, there was a statistically significant correlation between HGF expression levels and PF-2341066-induced inhibition of cell proliferation and cell survival (p&lt;0.01). Similarly, orthotopic xenografts derived from cell line with high HGF expression level were significantly stronger inhibited by oral administration of PF-2341066 to than xenografts derived from low-expressing HGF cells. Therefore, HGF co-expression is the best predictor of response to c-Met kinase inhibitors. Surprisingly, we also found that when glioma cells and stem cells are pretreated with HGF, PF-2341066 is able to induce significantly greater (34-79%) cell death than in non-pretreated cells (p&lt;0.01). The optimal time of pre-activation that achieved strongest sensitization to c-Met inhibitor-induced cell death was 2-4 hours. In vivo experiments showed that short-term bolus HGF pre-treatment of glioma stem cell-derived xenografts significantly sensitized the tumors to c-Met inhibition by PF-2341066. We therefore hypothesize that short-term exogenous activation of c-Met by HGF is able to trigger fast oncogene addition and therefore sensitize brain tumors to c-Met inhibitors. Overall, our data identify for the first time HGF co-expression as the determining factor in tumor sensitivity to c-Met kinase inhibitors and uncover HGF pre-treatment as a new strategy for enhancing the effects of the inhibitors. These findings have important practical implications for the efficient use of recently developed c-Met kinase inhibitors in cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1821. doi:1538-7445.AM2012-1821