Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma

Cheng, Hanyin; Terai, Mizue; Kageyama, Ken; Ozaki, Shinji; McCue, Peter A.; Sato, Takami; Aplin, Andrew E.

doi:10.1158/0008-5472.can-15-0370

Cited by 59 publications

(65 citation statements)

References 43 publications

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“…HGF is secreted by quiescent hepatic stellate cells. Consistent with the presence of HGF in tumor microenvironment, the majority of UM liver metastases express phosphorylated/activated cMET (20). Together, these results suggest that MEK inhibitors in combination with cMET targeting agents may have utility in advanced UM.…”

Section: Introductionmentioning

confidence: 78%

“…Inhibition of MEK1/2 with trametinib or selumetinib induces either cell cycle arrest or apoptosis in UM cell lines (7, 20); however, clinical studies in advanced stage UM patients indicate that MEK inhibitors have limited clinical benefit. Trametinib was ineffective in a phase I trial cohort of 16 metastatic UM patients (21).…”

Section: Introductionmentioning

confidence: 99%

“…In UM cell monocultures, hepatocyte growth factor (HGF) provides resistance to MEK inhibitors (20). HGF is secreted by quiescent hepatic stellate cells.…”

Section: Introductionmentioning

confidence: 99%

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

Cheng

Chua

Liao

et al. 2017

Molecular Cancer Therapeutics

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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.

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Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

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

Cheng

Chua

Liao

et al. 2017

Molecular Cancer Therapeutics

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“…The activation of HSCs from their resting/quiescent state to a profibrotic state triggers production of HGF, which results in recruitment of c-Met-expressing cells. It also contributes to proliferation of c-Metexpressing tumor cells and prevents apoptosis [14,30,35] . Furthermore, secretion of IL-8 from HSCs contributes to tumor angiogenesis, which facilitates the growth of metastases in the liver [28,36] .…”

Section: Hscsmentioning

confidence: 99%

Immunological aspect of the liver and metastatic uveal melanoma

Terai¹,

Mastrangleo²,

Sato³

2017

JCMT

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Uveal (eye) melanoma is the most common primary eye malignancy in adults. Despite optimal treatments for primary uveal melanoma, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Once hepatic metastasis develops, the survival of patients is generally short and currently available treatments fail to show meaningful improvement of survival. Recent development of immune checkpoint blockades revolutionized immunotherapy for metastatic cutaneous (skin) melanoma. Unfortunately, metastatic uveal melanoma is unresponsive to this approach, thus there is an unmet need to improve the treatment of metastatic uveal melanoma. One unique characteristic of uveal melanoma is that the majority of metastases first develop in the liver. The liver is highly specialized in development of immune tolerance to food-derived antigens and consequently serves a unique function in the immune system. Understanding the mechanisms by which the liver orchestrates immune-related responses is important to the development of an effective immunotherapy for hepatic metastases such as metastatic uveal melanoma. In this review article, the authors overview the immunological aspects of the liver and discuss approaches to improve immunotherapy for metastatic uveal melanoma. Key words:Uveal melanoma, metastasis, liver, liver microenvironment, immunotherapy ABSTRACTArticle history:

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“…nerve growth factor 1), which reactivate Erk1/2 in tumor cells (16) or provide ECM, which supports focal adhesions and survival signaling (17). We discovered the loss of pigment epithelial-derived factor (PEDF) as a critical step in melanoma transition to the aggressive, metastatic phenotype (18).…”

Section: Introductionmentioning

confidence: 99%

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

et al. 2016

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Summary Loss of pigment epithelium-derived factor (PEDF, SERPINF1) in cancer cells is associated with poor prognosis and metastasis, but the contribution of stromal PEDF to cancer evolution is poorly understood. Therefore, we investigated the role of fibroblast-derived PEDF in melanoma progression. We demonstrate that normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. Accordingly, mice with global PEDF knockout were more susceptible to melanoma metastasis. We also demonstrate that normal fibroblasts in close contact with PEDF-null melanoma cells lost PEDF expression and tumor suppressive properties. Further mechanistic investigations underlying the crosstalk between tumor and stromal cells revealed that melanoma cells produced PDGF-BB and TGF-β, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGF-β-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of interleukin-8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. Collectively, our results demonstrate that PEDF maintains tumor-suppressive functions in fibroblasts to prevent CAF conversion, and illustrate the mechanisms by which melanoma cells silence stromal PEDF to promote malignancy.

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Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma

Cited by 59 publications

References 43 publications

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

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

Immunological aspect of the liver and metastatic uveal melanoma

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

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