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Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma
Hanyin Cheng1, Vivian Chua1, Connie Liao1
1Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Abstract:
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.
Insights
Targeting HGF/cMET signaling overcomes MEK inhibitor resistance in metastatic uveal melanoma. Blocking cMET or PI3K pathways may improve treatment for liver metastases by inhibiting pro-survival signals.
Area of Science:
- Oncology
- Melanoma Research
- Drug Resistance Mechanisms
Background:
- Metastatic uveal melanoma has a poor prognosis with limited treatment options.
- Mitogen-activated protein kinase kinase (MEK) inhibitors show limited efficacy in uveal melanoma.
- Hepatocyte growth factor (HGF) signaling contributes to MEK inhibitor resistance.
Purpose of the Study:
- To investigate the mechanisms of HGF-mediated resistance to MEK inhibitors in metastatic uveal melanoma.
- To evaluate therapeutic strategies targeting HGF/cMET signaling and PI3K isoforms to overcome resistance.
Main Methods:
- Assessed the role of BH3-only proteins (Bim-EL, Bmf) in HGF-mediated resistance.
- Utilized anti-cMET antibody (LY2875358) and dual cMET/RON inhibitor (LY2801653) to target HGF/cMET signaling.
- Investigated PI3K isoform activation in mediating resistance.
- Evaluated combination therapy with LY2801653 and trametinib in metastatic uveal melanoma explants.
Main Results:
- HGF-mediated resistance to MEK inhibitors involves Bim-EL and Bmf.
- Targeting HGF/cMET signaling with LY2875358 or LY2801653 overcame trametinib resistance induced by HGF.
- PI3Kα/γ/δ activation mediated HGF-induced resistance.
- Combination of LY2801653 and trametinib reduced AKT phosphorylation and increased apoptosis.
Conclusions:
- HGF/cMET and PI3K signaling pathways are key mediators of MEK inhibitor resistance in uveal melanoma.
- Targeting cMET or PI3K isoforms offers a promising strategy to overcome intrinsic resistance in liver metastases.
- Combination therapy may improve outcomes for patients with metastatic uveal melanoma.
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