Kirsten L. Bryant, PhD

Overview

Aim: Prevention/Metabolism

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the United States, with a dismal 5-year survival rate of 13%. There is a dire, unmet need for new treatment strategies. Mutations in KRAS occur in over 90% of PDAC patients and play a crucial role in tumor progression and maintenance. Historically considered undruggable, the recent development of KRASG12C inhibitors established that RAS mutants could be targeted pharmacologically. This resulted in a surge in efforts to develop and improve drugs that target both other KRAS mutants and the RAS family of proto-oncogenes. Early evidence regarding RAS inhibitors in the clinic have shown that they are well-tolerated, with promising efficacy against RAS-driven PDAC.

The significance of this advance for the treatment of PDAC cannot be understated. However, resistance develops upon inhibition of RAS alone. It is imperative to understand how cells become resistant to RAS inhibition (RASi) to develop combination strategies to enhance the efficacy of RAS inhibitors in combination therapies. We hypothesize that dysregulation of core metabolic pathways contributes to RASi resistance and propose studies to understand how and to target the altered metabolism associated with RASi resistance.

It is well appreciated that metabolic rewiring occurs following direct RAS inhibition, therefore we also propose to identify the metabolic changes associated with RAS inhibition treatment compared to those present when cells become resistant to RASi. Our goal is to define the metabolic vulnerabilities associated with acute and prolonged RAS inhibition and identify targetable metabolic nodes. We expect to identify new, potential therapeutic targets and provide strong preliminary data for future NIH-grant submissions to support our goal to validate novel inhibitor combinations for the treatment of PDAC.