Optimizing MEK Inhibitors in NRAS Mutant Melanoma - Overcoming Resistance and Combination Strategies

Increased melanoma mortality is a cause for public health concern despite recent therapeutic advancements. NRAS mutant melanoma, specifically, remains elusive to existing targeted therapy options. Therefore, devising efficacious, safe, and durable treatment regimens for patients with this disease is of particular importance and urgency. In this thesis, we emphasize the impact of important patient and disease characteristics such as age, sex, and metastatic sites on patient outcomes. We summarize current mechanistic insights into how each factor can influence therapeutic response. Furthermore, we draw upon lessons from RAS-driven cancers and BRAF mutant and WT/WT melanomas and synthesize how these studies can contribute to understanding NRAS mutant melanoma. Specifically, we closely investigate the evidence and feasibility of direct RAS targeting, targeting RAS regulation, and targeting the MEK-ERK and other pathways. MEK inhibitors, small molecule drugs approved for the treatment of BRAF mutant melanoma, failed to meet critical efficacy end-points in clinical trials for NRAS mutant disease. Optimizing MEK inhibitors by overcoming resistance and or combining them with parallel pathway targeting and immunotherapies might present an attractive option for this group of melanoma patients. Our studies focused on this common theme, and discovered that metabolic rewiring contributes to MEK inhibitor resistance in NRAS mutant melanomas. We additionally found that upon inhibition of PDK1, a member of the PI3K-AKT pathway, a panel of NRAS mutant melanoma cell lines was sensitized to MEK targeting. Lastly, we characterized a syngeneic model of NRAS mutant mouse melanoma which constituted an indispensable resource for the pre-clinical testing of therapeutic candidates in physiologically relevant animal models. Together, our studies converge on critical research themes of metabolism, mTOR signaling, and the crosstalk between targeted therapy and the immune system, and form the basis for future investigation. This thesis incorporates clinical observations and molecular evidence, with the goals of achieving highly translational research, bridging the gaps between the medical and scientific communities, and ultimately bringing about tangible outcomes for NRAS mutant melanoma patients