Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma

In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα// isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver. Mol Cancer Ther; 16(3); 516–28. ©2017 AACR.

Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Cheng, H., Chua, V., Liao, C., Purwin, T. J., Terai, M., Kageyama, K., Davies, M. A., Sato, T., Aplin, A. E. Tags: Cancer Biology and Signal Transduction Source Type: research