Exploiting tumor microenvironment-mediated mechanisms of therapeutic resistance in Ras/MAPK-altered solid cancers

Abstract

Ras/MAPK alterations drive roughly 40% of human cancers which vary in phenotype, aggressiveness, and response to therapy. This thesis asks how oncogenic Ras/MAPK signaling interacts with distinct components of the tumor microenvironment to drive therapy resistance in two cancer types. The negative regulator of Ras, Neurofibromin 1 (NF1), is altered in about 20% of tubo-ovarian high-grade serous carcinomas (HGSC). We use in vitro and in vivo models of ovarian cancer to study how cell-cell interactions between adipocytes and cancer cells impact therapy response. NF1 alteration exacerbates adipocyte-mediated resistance to standard-of-care chemotherapy. Downstream of Ras, activating mutations in the BRAF kinase are present in over half of cutaneous melanoma cases. Specifically, BRAF^[V600E] hyperactivates downstream MAPK signaling, which is the target of several generations of small-molecule inhibitors. MAPK-targeted therapies show initial efficacy in patients, but acquired resistance is a major clinical threat. Focusing on the role of the immune compartment in treatment-refractory melanoma, we show that targeting the novel immune checkpoint, P-selectin glycoprotein ligand-1 (PSGL-1), delays relapse to BRAF/MEK-targeted therapy in pre-clinical models. Combined BRAF/MEK and PSGL-1 targeting provides a durable anti-tumor response through enhanced functionality and a memory-like phenotype in CD8⁺ T cell subsets. Together, these studies address how tumor-cell intrinsic and extrinsic factors interact under the selective pressure of therapy in Ras/MAPK-altered solid tumors. We provide insight on how genetic alterations affect interactions between cancer cells and their environment and how these dynamics reveal resistance mechanisms that can be exploited for therapeutic benefit.