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

Abstract

Metastatic uveal melanoma (UM) patients usually die within one 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 UM patients. Our previous work showed that HGF signaling elicits resistance to MEK inhibitors in metastatic UM. 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 pro-apoptotic PARP cleavage in metastatic UM explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic UM may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in liver.

Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma

“…In addition, our findings indicated that stromal FGF2 rescues BET inhibitor effects in metastatic UM cells and also showed upregulation of FGFR expression as an adaptive response to BET inhibitors in cell lines and patient tumor samples. Previously, we reported that HGF secreted from HSCs rescued metastatic UM cells from the growth inhibitory effects of a MEK inhibitor, trametinib, and was associated with paracrine activation of cMET and PI3K/AKT pathways (Cheng et al, 2015(Cheng et al, , 2017. Our findings highlight the ability of stromal cells in the TME to mediate resistance to targeted inhibitors in UM.…”

Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma

“…Hepatocyte growth factor (HGF) provided resistance to trametinib growth inhibitory effects in metastatic UM cell lines and targeting of cMET (the receptor for HGF) enhanced the effects of trametinib in metastatic UM (40, 46). HGF-CMET signaling induced downregulation of BH3 pro-apoptotic proteins, BIM and BMF, which correlated with HGF-mediated inhibition of apoptosis in trametinib-treated cultures (46).…”

“…Hepatocyte growth factor (HGF) provided resistance to trametinib growth inhibitory effects in metastatic UM cell lines and targeting of cMET (the receptor for HGF) enhanced the effects of trametinib in metastatic UM (40, 46). HGF-CMET signaling induced downregulation of BH3 pro-apoptotic proteins, BIM and BMF, which correlated with HGF-mediated inhibition of apoptosis in trametinib-treated cultures (46). Importantly, HGF is secreted by quiescent hepatic stellate cells that can be found in the liver microenvironment and phosphorylated/activated cMET is detected in the majority of UM liver metastases (40, 46).…”

“…HGF-CMET signaling induced downregulation of BH3 pro-apoptotic proteins, BIM and BMF, which correlated with HGF-mediated inhibition of apoptosis in trametinib-treated cultures (46). Importantly, HGF is secreted by quiescent hepatic stellate cells that can be found in the liver microenvironment and phosphorylated/activated cMET is detected in the majority of UM liver metastases (40, 46). HGF promotes activation of the PI3K/AKT pathway as a mechanism of resistance to trametinib and the increase in phosphorylation of AKT is mediated by PI3K isoforms α, δ and γ.…”

“…HGF promotes activation of the PI3K/AKT pathway as a mechanism of resistance to trametinib and the increase in phosphorylation of AKT is mediated by PI3K isoforms α, δ and γ. Use of a β-sparing PI3K inhibitor, GDC0032, reversed HGF-induced resistance to trametinib (46). These findings support an earlier study which reported the combination of MEK and PI3K inhibitors for UM and these agents induce marked early apoptosis in GNAQ mutant UM cell lines compared to the inhibitors alone which have moderate effects on apoptosis (40, 41).…”