CCSG Pilot: Uncovering Signaling Pathways Driving High Melanoma Mortality in Rural Kentucky

SCIENTIFIC ABSTRACT Melanoma cases continue to rise, and despite new treatments, the disease remains deadly if it has metastasized. Kentucky is ranked 10th in melanoma incidence and 7th in mortality, and melanoma is even more deadly in rural KY. Although more common in non-Hispanic whites, melanoma is more deadly in Blacks, Hispanics, Asians and Native Americans. Patients with metastatic melanoma are treated 1st line with immune- checkpoint blockade (ICB); however, ICB only works for some patients, and others cannot tolerate the side- effects. Melanomas with BRAF mutations are treated 2nd line with BRAF/MEK inhibitors (targeted therapy). While effective initially, the vast majority only survive 12-14 months. For melanomas harboring NRAS mutations, effective 2nd line targeted agents do not exist. Tumor-infiltrating lymphocyte (TIL) therapy is an exciting new option, but it is expensive, requires hospitalization, has significant side-effects, and usually is not curative. Once melanomas become resistant to therapy, they are highly aggressive and patients rapidly succumb to the disease. Thus, it is critical to understand the molecular mechanisms underlying response to therapy, resistance, and metastatic progression. Here, we show that the ABL1 and ABL2 tyrosine kinases promote invasion and metastasis following acquired resistance to targeted therapy. ABL1/2 also promote expression of ZEB1 and N-cadherin, proteins with known roles in invasion and metastasis. Based on our preliminary data, the central hypothesis is that ABL1/2 drive melanoma invasion and metastasis during resistance by protecting ZEB1 and N-cadherin from degradation, and the ABL/ZEB1/N-cadherin pathway is upregulated in melanomas from patients residing in rural Kentucky and in Blacks/Hispanics. Our long-term goal is to better understand what drives melanoma aggressiveness during resistance so that we can design new drug combinations. To achieve our objective, Aim 1 (supported by Dr. Wang, Biostatistics, and Flow SRs) will utilize biochemical, cell biological assays and in vitro and in vivo models to define mechanisms by which ABL1/2 stabilize ZEB1 and N-cadherin and drive invasion and metastasis. Aim 2 (supported by Drs. Huang and Richards, and Biospecimen and Biostatistics SRs) will utilize the SEER database, RNAseq data from ORIEN samples, and paraffin-embedded melanoma samples to determine whether melanomas are more aggressive/metastatic in our region and have higher activation of the ABL->ZEB1->N-cadherin signaling pathway in melanomas from patients living in rural KY. Moreover, this aim also includes a population study (Drs. Stapleton, Arays) designed to understand the challenges facing patients with metastatic melanoma, and factors influencing their treatment decisions. Finally, our study includes three patient advocates (two survivors and one caregiver) who will interact with the study team, provide input into the experimental design and patient recruitment, and assist with dissemination of findings via a lay summary infographic, and presentation to the Kentucky Oncology Nurses Symposium (KONES) and the MCCAN “Spotlight” series.