Personalized targeting of anti-apoptosis pathways to overcome therapeutic resistance in melanoma

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Project Summary – Project 2 Melanoma is an aggressive skin cancer and is only second in the number of life-years lost per cancer- related death in the US. Although targeted therapies with combinations of BRAF and MEK inhibitors (BRAFi+MEKi) achieve very high clinical response rates in BRAFV600-mutant melanoma, ultimately ~80% of patients develop resistance. Notably, there are no approved targeted therapies for BRAFWT melanoma patients. Further, only ~40% of metastatic melanomas achieve durable responses to immune checkpoint inhibitors. Thus, there is a significant unmet clinical need to identify novel strategies to prevent/counteract resistance to clinically approved targeted therapies in BRAFV600-mutant melanoma patients, and to develop effective therapeutic approaches for BRAFWT cutaneous and non-cutaneous melanomas like acral melanomas which are under- represented in clinical studies. Therapeutic resistance in melanoma is mostly mediated by proteins that prevent apoptosis of the tumor cells and promote their survival. Therefore, to address the unmet needs for melanoma therapy, we will develop personalized therapeutic approaches targeting aberrant anti-apoptotic pathways driving drug resistance. We hypothesize that inhibiting survival mechanisms in targeted therapy-resistant melanoma will sensitize them to undergo apoptosis, leading to tumor regression. We will test this hypothesis with two aims. Aim 1, is based on our preliminary results showing that BRAFV600-mutant melanoma PDXs with high MCL1 are resistant to BRAFi+MEKi. Our preliminary studies also show that MCL1Hi tumors are sensitive to MCL1 inhibition. We will optimize MCL1 inhibition in combination with MAPKi to overcome drug resistance. In Aim 2, we will exploit the presence of somatic mutations in DNA damage repair (DDR) genes in BRAFWT melanomas and will determine the efficacy of DDR inhibitors in PDXs selected based on alterations in DDR genes. Importantly, as a large percentage of acral melanomas are BRAFWT and are resistant to current therapies, we will include acral melanoma PDXs in this study and determine the therapeutic value of DDR inhibitors. For both aims, we will use a novel in vitro MicroOrganoSphere platform (Xilis Inc.) and in vivo tumor growth inhibition studies in our large collection of molecularly characterized PDXs, to identify the most effective treatments that can be translated into future clinical trials. We will then perform whole tumor/spatial/single cell molecular analyses on responders and non-responders to identify biomarkers of response and resistance. To achieve these goals, we have assembled an outstanding team of investigators with diverse and complementary expertise. Together, our expertise and resources will facilitate optimization and prioritization of the best combination treatments to effectively address the two urgent unmet needs for melanoma patients.