Melanoma is the deadliest form of skin cancer.
We aim to understand mechanisms underlying oncogenic signaling and drug resistance in melanoma in order to improve the current treatment options. The serine/threonine kinase, BRAF, is somatically mutated in ~50% of melanomas and drives hyper-activation of MEK-ERK1/2 signaling, aberrant growth and invasion. While BRAF and MEK inhibitors are now first-line therapy for advanced-stage mutant V600E BRAF melanomas, they only delay mortality. Thus, we must understand how to build on BRAF+MEK inhibitor treatments and determine how to combine them with immune checkpoint agents, which remove the blocks on T cell action. In the previous cycle of this grant, we showed that up-regulation of FOXD3- ErbB3 signaling is an adaptive response to BRAF inhibitors that promotes a state of drug tolerance in mutant BRAF melanoma. Furthermore, we showed that inhibition of ErbB3 enhanced the effects of BRAF inhibitors in mutant BRAF melanomas in vivo. In this current proposal, we aim to identify mechanisms regulating FOXD3 in mutant BRAF melanomas, test the possibility that epigenetic BET/BRD inhibitors will block adaptive responses to BRAF+MEK inhibitors and alter the tumor microenvironment, and determine how FOXD3 expression alters the infiltration/activation status of tumor-associated immune cell populations and the expression of putative immune checkpoint proteins. At the completion of our experiments, we expect to have identified tumor and stromal markers for adaptive responses to targeted therapy and informed future combinatorial targeted inhibitor, epigenetic inhibitor and immune-based therapeutic strategies in mutant BRAF melanoma.
New cancer treatments based on targeted small molecule inhibitors and immunotherapy have increased long- term survival for advanced skin melanoma patients. However, the majority of patients still do not benefit and many of the regimens are associated with significant toxicities as well as high health care delivery costs. Our proposed research seeks to understand the adaptive response of melanoma cells that hinders effective treatment. Ultimately, we aim to identify biomarkers for the adaptive response, leading to improved inhibitor- based and immune-based therapeutic strategies for melanoma, while also reducing undesirable side effects and health care costs.
|Romano, Gabriele; Chen, Pei-Ling; Song, Ping et al. (2018) A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling. Cancer Discov 8:556-567|
|Hartsough, Edward J; Kugel 3rd, Curtis H; Vido, Michael J et al. (2018) Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo. Mol Cancer Ther 17:84-95|
|Teh, Jessica L F; Aplin, Andrew E (2018) Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment. Clin Cancer Res :|
|Teh, Jessica L F; Aplin, Andrew E (2018) Playing the Melanoma Endgame. Clin Cancer Res 24:4629-4630|
|Behera, Reeti; Kaur, Amanpreet; Webster, Marie R et al. (2017) Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho. Clin Cancer Res 23:3181-3190|
|Vu, Ha Linh; Aplin, Andrew E (2016) Targeting mutant NRAS signaling pathways in melanoma. Pharmacol Res 107:111-116|
|Hartsough, Edward J; Aplin, Andrew E (2016) Of Mice and Melanoma: PDX System for Modeling Personalized Medicine. Clin Cancer Res 22:1550-2|
|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|
|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|
|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|
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