Overview
KRAS mutations are present in more than 90% of pancreatic ductal adenocarcinomas. Our lab is at the forefront of targeting KRAS G12D — the most common substitution variant in pancreatic cancer, found in roughly 40% of patients.
First-in-class therapeutics
We led the first-in-human trial of setidegrasib (ASP3082), a first-in-class KRAS G12D targeted protein degrader, published in the New England Journal of Medicine (2026).
We also contributed to the phase 1–2 study of daraxonrasib (RMC-6236), an oral RAS(ON) multiselective inhibitor that targets GTP-bound mutant and wild-type RAS, with encouraging activity in previously treated RAS-mutated PDAC.
Degraders vs. inhibitors
Targeted protein degraders remove the mutant KRAS protein entirely, which can suppress signaling more completely and may delay the reactivation seen with occupancy-based inhibitors.
RAS(ON) multiselective inhibitors instead target the active, GTP-bound state across mutant and wild-type RAS, broadening the population that might respond. Comparing these mechanisms head-to-head is central to our program.
Genomics of KRAS
Beyond drugging KRAS, we characterise how specific KRAS mutants and mutant dosage shape clinical outcomes and biology, informing which patients should receive which RAS-directed therapy.
Open questions
What are the dominant resistance mechanisms to KRAS G12D-directed therapy, and can combination strategies delay or prevent them?
How can screening and DDR- or immune-directed programs be combined with RAS-targeted agents to convert responses into durable remissions?