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
Dr. Park was first author of 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). At the selected 600-mg dose, 5 of 21 heavily pretreated metastatic PDAC patients had an objective response.
He 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. In the second-line RAS G12 cohort, objective response was 35%, median PFS was 8.5 months, and median OS was 13.1 months; randomized trials are needed to establish comparative benefit.
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. Serial ctDNA analyses in first-line daraxonrasib-plus-chemotherapy work have also shown deep molecular responses, a promising biomarker signal that still requires prospective validation as a clinical endpoint.
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?