American Association for Cancer Research
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Supplemental Figure Legends from Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma

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journal contribution
posted on 2023-04-03, 16:03 authored by Hanyin Cheng, Vivian Chua, Connie Liao, Timothy J. Purwin, Mizue Terai, Ken Kageyama, Michael A. Davies, Takami Sato, Andrew E. Aplin

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Dr. Ralph and Marian Falk Medical Research Trust

Provost's office at Thomas Jefferson University

Pennsylvania Department of Health

NIH/National Cancer Institute

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Cancer Center Support Grant

National Cancer Institute

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Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF–mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to 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/γ/δ 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.

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