Developing New Therapies for Metatsic Melanoma

Lay Abstract In 2017, the Markey Women Strong group awarded me their inaugural grant to fund my research on melanoma metastasis. I cannot put into words the impact that this funding had on my career. I was in-between funding, having just missed the payline on several grants. But, more importantly, my interaction with patients and family members touched by melanoma made an indelible mark on my resolve to perform research that results in new therapies for this deadly disease. The results from experiments performed with MWS funding, led to an NCI R01 award to understand how one type of melanoma, those containing a mutation in a gene called BRAF, spreads to other organ sites (metastasis) and resists the effects of drugs targeting the BRAF pathway (BRAF/MEK inhibitors; a.k.a. MAPK inhibitors). Melanomas initially respond to these therapies and shrink and sometimes even appear to disappear; however, in the vast majority of cases, the melanomas develop resistance to the drugs, come back with a vengeance and quickly kill the patient. We made the seminal discovery that ABL proteins (ABL1, ABL2) promote resistance to BRAF/MEK inhibitors. When we treat animals harboring BRAF-mutant melanomas that have developed resistance to BRAF/MEK inhibitors, with a drug that inhibits the ABL proteins, the tumors dissolve away. More importantly, when we treat the mice up front with the ABL inhibitor in combination with the BRAF/MEK inhibitors, the ABL inhibitor prevents the BRAF/MEK inhibitor resistance from developing in the first place. These exciting data, spurred by MWS funding, led to a multi-site clinical trial to test the drug combination in patients. The current proposal is focused on a different melanoma subtype, those driven mutant NRAS. NRAS-mutant melanomas are more aggressive and more deadly than the BRAF-mutant subtype, and there are fewer treatment options as they do not respond to MAPK inhibitors. The only efficacious drugs are immunotherapies (immune-checkpoint inhibitors, ICI) which are only effective for some patients. This proposal aims to understand why NRAS-driven melanomas are resistant to drugs targeting MEK since, like BRAF, NRAS also activates MEK. We show that ABL and DDR1 proteins play a critical role in the non-responsiveness of NRAS-mutant melanomas to MEK inhibitors. Thus, Aim 1 focuses on understanding how ABL/DDR drive MEKi resistance, with the goal of designing a new targeted therapy (drugs inhibiting a pathway changed in cancer) for patients with metastatic NRAS-mutant melanoma. Aim 2 will test the hypothesis that ABL inhibitors also sensitize NRAS-mutant melanomas to ICI based on our preliminary data demonstrating that ABL proteins impact pathways known to impact ICI sensitivity. The Aim also will utilize a cutting edge fairly new technique (single-cell RNAseq) to assess how ABL/DDR inhibitors impact immune (and other) cells in the melanoma microenvironment (region around the tumor) and how these cells contribute to the sensitivity of melanomas to therapy. If successful, data resulting from this funding will result in new clinical trials for patients harboring this aggressive and deadly disease, who have few therapeutic options.