Clinical Fellow, Dana Farber Cancer Institute
Development of novel KRAS/FGFR combination therapies for treatment of pancreatic cancer
Overview
Aim: Prevention/Metabolism
Pancreatic cancer is a leading cause of cancer-related mortality in the US and is largely driven by KRAS mutations. While KRAS inhibitors are in trials in pancreatic cancer, resistance is common, often mediated by parallel RTK/PI3K pathway activation or persistent KRAS activity. This highlights the need for combination therapeutics to prevent resistance, as well as entirely new therapeutic strategies.
To address this need, we developed a dual-gene CRISPR knockout library targeting 10,296 pairwise gene combinations within the RAS pathway and related signaling pathways. We screened this library in a panel of cell lines, identifying synergistic gene interactions between KRAS and FGFR signaling in KRAS-mutant pancreatic cancer cell lines. We found that combined KRAS and FGFR signaling pathway loss was very effective at killing pancreatic cancer cells. Here, we seek to explore this finding, elucidating the mechanisms underlying the synergy of dual KRAS/FGFR loss.
There are several FDA-approved FGFR inhibitors and we will identify the most synergistic combination of existing KRAS and FGFR inhibitors. We will then develop this combination for potential clinical use by assessing its efficacy in >900 cancer cell line models and in mice. Positive results will nominate dual KRAS/FGFR inhibition as a clinical combination for treatment of pancreatic cancer and this proposal will identify the most promising existing KRAS and FGFR drugs. These drugs are in clinical trials or approved and thus are poised for rapid clinical translation.
