Expression of insulin‐like growth factor‐1 receptor in metastatic uveal melanoma and implications for potential autocrine and paracrine tumor cell growth

Yoshida, Makoto; Selvan, Senthamil R.; McCue, Peter A.; DeAngelis, Tiziana; Baserga, Renato; Fujii, Ami; Rui, Hallgeir; Mastrangelo, Michael J.; Sato, Takami

doi:10.1111/pcmr.12206

Cited by 46 publications

(43 citation statements)

References 46 publications

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“…We determined the effects of clinically relevant, small molecule MEK inhibitors in three genetically characterized cells lines derived from UM metastases: UM001 was established from liver metastasis and harbors a GNAQ Q209P mutation; UM003 was generated from retroperitoneal metastasis and harbors a GNAQ Q209L mutation (25) and UM004 cells were established from orbital metastasis and harbor a GNAQ Q209P mutation (Supp. Fig.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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Uveal melanoma (UM) patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic UM patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic UM cell lines to clinical grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1, and sustained HGF mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF respectively, overcomes resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. UM xenografts growing in the liver in vivo and a subset of liver metastases of UM patients express activated forms of ERBB2 (the co-receptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic UM.

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Section: Resultsmentioning

confidence: 99%

“…The mutational status of UM001 and UM003 cells were described previously (25). Mutational analysis of GNAQ was performed by Sanger sequencing.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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“…In the selective and rapid growth of uveal melanoma cells in the liver, IGF-1/IGF-1 receptor interactions seem to play a critical role by 'paracrine' stimulation. Yoshida et al [31] investigated the IGF-1 receptor pattern in metastatic liver tissue, and found that the cells proliferated in response to exogenous and endogenous IGF-1. Our study also showed that insulin resistance and basal insulin levels were significantly higher in the uveal melanoma group compared with the controls.…”

Section: Discussionmentioning

confidence: 98%

Serum adiponectin, insulin resistance, and uveal melanoma

Sevim

Kıratlı

2016

Melanoma Research

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To investigate the status of insulin resistance, metabolic syndrome, dyslipidemia, and serum adiponectin levels in patients with uveal melanoma and choroidal nevus were investigated. Our study included 86 patients with uveal melanoma, 38 patients with choroidal nevus, and 86 controls. Uveal melanomas were classified as small, medium, and large on the basis of Collaborative Ocular Melanoma Study (COMS) criteria. Patients with uveal melanoma had significantly higher homeostatic model assessment scores compared with patients with choroidal nevus (P<0.001). Patients with uveal melanoma and choroidal nevus had significantly lower levels of serum adiponectin compared with controls (P<0.001). Patients with uveal melanoma who developed systemic metastases had significantly lower levels of serum adiponectin levels compared with patients with nonmetastases during follow-up (P=0.018). When the largest tumors (COMS III) were compared, ciliary body melanomas were associated with significantly lower levels of serum adiponectin than choroidal melanomas. In patients who were treated with enucleation, epitheloid predominant and mixed cell-type tumors were associated with lower levels of serum adiponectin compared with tumors with spindle cell type, but this did not reach statistical significance. By providing an antiapoptotic and proangiogenic environment, low serum adiponectin levels and insulin resistance may play a role in promoting the growth of uveal melanocytic tumors and may contribute toward a more aggressive clinical course, adversely affecting the prognosis.

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“…UM001 and UM004 cells were derived from liver and orbital metastases of human UM, respectively; both harbor GNAQ Q209L mutations (20, 24). UM001 cells were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated FBS, 10% non-essential amino acids, 2 mM L-glutamine and 10 mM Hepes buffer.…”

Section: Methodsmentioning

confidence: 99%

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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Expression of insulin‐like growth factor‐1 receptor in metastatic uveal melanoma and implications for potential autocrine and paracrine tumor cell growth

Cited by 46 publications

References 46 publications

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

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

Serum adiponectin, insulin resistance, and uveal melanoma

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

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