UNC Lineberger researchers Channing J. Der, PhD, and Jen Jen Yeh, MD, have published an editorial in the New England Journal of Medicine as part of the journal’s Science Behind the Study series. Their paper, “Advances in RAS Therapeutics for Pancreatic Cancer,” elucidates the scientific foundation for a landmark clinical study evaluating daraxonrasib, a first-in-class drug targeting KRAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC).
KRAS mutations are present in more than 90 percent of PDAC, making KRAS the dominant driver of this devastating disease. Despite its central role in tumor initiation and progression, KRAS was long considered undruggable. This reputation stood for nearly three decades due to the protein’s structural and biochemical properties that make it exceptionally resistant to small-molecule inhibition.
Der and Yeh trace the scientific turning point to 2013, when researchers discovered the switch-II pocket, a previously hidden druggable pocket in the KRAS protein specific to the G12C mutation. This finding resulted in the FDA approvals of sotorasib and adagrasib for KRAS G12C-mutant non-small cell lung cancer and fundamentally reconceived RAS as a pharmacologically controllable target.
They then explain how a second, independent line of inquiry led to the development of a novel class of inhibitors that target RAS in its active, GTP-bound “ON” state. Unlike earlier approved drugs, which lock KRAS in its inactive “OFF” state and are selective for the G12C mutation, daraxonrasib blocks RAS from engaging downstream effectors. Critically, daraxonrasib recognizes all RAS isoforms and mutation types, broadening its potential applicability far beyond G12C-mutant cancers — a major advantage in PDAC, where G12C mutations account for fewer than 2 percent of cases.
The clinical study contextualized in this editorial reported a response rate of up to 35 percent in previously treated patients with metastatic PDAC, with a median duration of response of 8.2 months. Der and Yeh note that while these results are unprecedented for a single-agent small-molecule inhibitor in pancreatic cancer, resistance to daraxonrasib does emerge. Next steps will require understanding resistance mechanisms and rationally designing combination regimens, and multiple clinical trials are actively evaluating daraxonrasib in combination with other targeted agents and chemotherapy.
You can read the full editorial here.
— Tyler Rice, UNC Lineberger Pancreatic Cancer Center of Excellence