TY - JOUR
T1 - Co-Targeting HGF/cMET Signaling with MEK Inhibitors in metastatic uveal melanoma
AU - Cheng, Hanyin
AU - Chua, Vivian
AU - Liao, Connie
AU - Purwin, Timothy J.
AU - Terai, Mizue
AU - Kageyama, Ken
AU - Davies, Michael A.
AU - Sato, Takami
AU - Aplin, Andrew E.
N1 - Publisher Copyright:
© 2017 AACR.
PY - 2017/3
Y1 - 2017/3
N2 - 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 PI3Ka/g/d 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.
AB - 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 PI3Ka/g/d 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.
UR - http://www.scopus.com/inward/record.url?scp=85014712894&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014712894&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-16-0552
DO - 10.1158/1535-7163.MCT-16-0552
M3 - Article
C2 - 28138035
AN - SCOPUS:85014712894
SN - 1535-7163
VL - 16
SP - 516
EP - 528
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 3
ER -