Despite recent major advances in targeted therapy for melanoma, the nearly universal eventual acquisition of drug resistance remains a major hurdle that prevents durable gains in patient survival. To address this critical unmet need, we have recently used patient samples and model systems to identify S6K1 as a critical counter-resistance therapy target that lies at the downstream convergence point of the MAPK, CDK4/6, and PI3K pathways. Importantly, these are the primary drivers of both melanomagenesis and of known BRAF and MEK inhibitor resistance mechanisms, positing S6K1, an understudied drug target, as a potential broad-use salvage and/or frontline therapy. Our preliminary data is consistent with this hypothesis, as pharmacological S6K1 inhibition reversed MAPK inhibitor resistance in several drug and genetic contexts. Our central hypothesis is that understanding the mechanistic basis and clinical applicability of S6K1 inhibition in melanoma will allow for improved design of next-generation S6K1 inhibitors and combination therapies, as well as a deeper functional understanding of drug resistance mechanisms operating through and downstream of S6K1.
Specific Aim 1 will focus on developing S6K1 as a key drug target in the contexts of both drug resistance and tumor initiation, and its clinical relevance will be interrogated in a series of clinical biopsies.
Specific Aim 2 will determine the oncogenic mechanisms downstream of S6K1, with distinct focuses on its impact on cell cycle and metabolism. Overall, successful completion of this study will provide an evidential basis for S6K1 as a promising broad-use therapeutic target, with a mechanistic underpinning to further refine future designs and uses of pharmacological S6K inhibitors.
BRAF and MEK inhibitor therapies are often potent against melanoma, but patients nearly always eventually develop drug resistance. We have identified S6K1, an understudied drug target, as a potential broad-use counter-resistance therapy, as it can block most known resistance mechanisms. In this proposal, we will cement a role of S6K1 as a key drug target in melanoma by conducting extensive drug testing, examining its correlation with patient outcomes, and exploring the mechanisms of how S6K1 drives drug resistance.
