Melanoma is the deadliest form of skin cancer and represents a paradigm for chemo-resistance.
We aim to understand resistance mechanisms in melanoma in order to provide the basis for improved targeted therapeutic strategies. The serine/threonine kinase, B-RAF, is somatically mutated in 40-60% of melanomas. Mutant B- RAF hyper-activates MEK-ERK1/2 signaling and is required for melanoma growth and invasion. A phase I clinical trial with the RAF inhibitor, PLX4032 (RG7204/Vemurafenib) yielded promising results in mutant B-RAF melanoma patients. However, 19% of patients were intrinsically resistant to B-RAF inhibitors and most initial responders are now relapsing from acquired drug resistance. An inability to eradicate tumors is also evident using in vivo models in which RAF/MEK inhibitors potently inhibit mutant B-RAF-driven melanoma growth but treatment cessation results in rapid tumor re-growth. The mechanisms underlying resistance to B-RAF inhibitors are unknown and must be elucidated to optimize future clinical trials. Our studies will focus on the stemness factor, FOXD3, which is up-regulated following B-RAF inhibition in mutant B-RAF melanoma cells.
In Aim 1 of this application, we will determine the role of FOXD3 in melanoma growth and resistance to B-RAF inhibitors in vivo.
In Aim 2, we will identify mechanisms regulating FOXD3 in mutant B-RAF melanomas.
In Aim 3, we will determine the role of ERBB3, a direct target of FOXD3, in eliciting the effects of RAF inhibitors. Our experimental approaches are innovative in that we modulate B-RAF activity using clinical grade inhibitors and molecular biology approaches in physiologically relevant in vitro and in vivo models. At the completion of our experiments, we expect to have identified a novel resistance-promoting mechanism and provided evidence for utilizing FOXD3 and/or ERBB3 as a biomarker for B-RAF inhibitor resistant melanoma cells.
Melanoma is the deadliest form of skin cancer and current treatment options are poor. Our application focuses on recent advances in therapeutics designed to target a signaling protein, B-RAF that is expressed in a mutant form in approximately 40-60% of melanomas. An inhibitor of RAF elicits short term clinical benefit in the majority of melanoma patients;however, mechanisms of intrinsic (primary) resistance and acquired (secondary) resistance are apparent. We expect that our results will lead to an understanding of resistance mechanisms in this highly aggressive cancer.
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|Vu, Ha Linh; Aplin, Andrew E (2016) Targeting mutant NRAS signaling pathways in melanoma. Pharmacol Res 107:111-6|
|Cheng, Hanyin; Terai, Mizue; Kageyama, Ken et al. (2015) Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma. Cancer Res 75:2737-48|
|Capparelli, Claudia; Rosenbaum, Sheera; Berger, Adam C et al. (2015) Fibroblast-derived neuregulin 1 promotes compensatory ErbB3 receptor signaling in mutant BRAF melanoma. J Biol Chem 290:24267-77|
|Talati, Pooja G; Gu, Lei; Ellsworth, Elyse M et al. (2015) Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer. Am J Pathol 185:2505-22|
|Capparelli, Claudia; Rosenbaum, Sheera; Berman-Booty, Lisa D et al. (2015) ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas. Cancer Res 75:3554-67|
|Kubic, Jennifer D; Lui, Jason W; Little, Elizabeth C et al. (2015) PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma. J Biol Chem 290:21901-14|
|Shao, Yongping; Le, Kaitlyn; Cheng, Hanyin et al. (2015) NF-ÎºB Regulation of c-FLIP Promotes TNFÎ±-Mediated RAF Inhibitor Resistance in Melanoma. J Invest Dermatol 135:1839-48|
|Hartsough, Edward J; Basile, Kevin J; Aplin, Andrew E (2014) Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma. Mol Cancer Res 12:795-802|
|Sanchez, Ileine M; Aplin, Andrew E (2014) Hippo: hungry, hungry for melanoma invasion. J Invest Dermatol 134:14-6|
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