Research Focus

KRAS is the most frequently mutated oncogene in pancreatic, lung, and colon cancers, which represent the three most deadly cancers in the United States. For that reason, KRAS has been deemed the “beating heart of cancer”, and developing drugs towards KRAS has been deemed the “holy grail” of cancer research. Unfortunately, for almost four decades, KRAS remained “undruggable.” However, due to phenomenal recent advancements in the field, there are now FDA-approved KRAS inhibitors that target one particular KRAS mutation (KRAS G12C). However, this class of inhibitors will be limited in pancreatic cancer patients for two main reasons. First, although almost all pancreatic cancer patients have a mutation in KRAS, only 1% of those have a KRAS G12C mutation. Therefore, a major unmet clinical need for the field is the development of KRAS inhibitors that target the other 99% of pancreatic cancer patients with KRAS mutations. Second, as with all targeted therapies, patients treated with KRAS inhibitors will invariably relapse due to treatment-induced resistance. The overarching goal of the Waters Lab is to address these limitations with the aim of extending the efficacy of KRAS inhibitors in the clinic and the lives of patients with pancreatic cancer.

Our research focuses on utilizing first-in-class KRAS inhibitors relevant to all pancreatic cancer patients, with the goal of understanding the molecular consequences and resistance mechanisms to KRAS inhibitors in pancreatic cancer. Our lab utilizes a panel of pancreatic cancer cell lines, patient-derived pancreatic organoids, and multiple mouse models to accomplish these goals. We use a combination of genetic (CRISPR/Cas9, siRNA, shRNA) and pharmacologic (FDA-approved, clinical candidate, and preclinical inhibitors) approaches to fundamentally understand how pancreatic cancer cells respond and adapt to direct KRAS inhibition, to identify and mechanistically dissect therapeutic vulnerabilities. We are heavily focused on understanding both inhibitor-specific and KRAS-mutation specific resistance mechanisms. We collaborate with pharmaceutical companies, external academic labs, and outstanding clinical and basic research programs within the University of Cincinnati.