Targeting KRAS in Pancreatic Cancer: What is Daraxonrasib’s Mechanism of Action?

At the 2026 American Association for Cancer Research (AACR) Annual Meeting, Asfar Azmi, PhD, shared 2 posters on novel treatment combinations in pancreatic cancer.^1,2 Both of those combinations featured KRAS-targeted therapies, and for decades, KRAS was considered an undruggable target due to its unique structure, which lacks the deep binding pockets typically required for small-molecule therapeutics.

However, in April 2026, results from the phase 3 RASolute 302 (NCT06625320) trial reported a significant doubling of overall survival with daraxonrasib compared with standard of care.³ Azmi detailed the innovative biochemistry developed to address this challenge. Daraxonrasib utilizes a tricomplex mechanism of action: the drug first binds to a chaperone protein, cyclophilin A, to form a bicomplex. This bicomplex then associates with the RAS protein to form a tricomplex, effectively inhibiting its oncogenic activity.

This approach has proven particularly effective in overcoming the dense stroma that characterizes pancreatic tumors, which historically has impeded the penetration of various therapeutic agents.

Azmi characterized these results as a remarkable milestone for patients with metastatic pancreatic cancer who have progressed on initial chemotherapy. He further expressed that this was one of the most promising therapeutic advances in the pancreatic cancer space in approximately 20 years.

Azmi is a professor of oncology at Wayne State University School of Medicine and the director of Pancreas Cancer Research at the Karmanos Cancer Institute in Detroit, Michigan.

Transcript:

This is fabulous news, and it surprised all of us who have been working in the KRAS field for a long time. KRAS was considered undruggable for a long time because this was a protein that did not have any deep pocket in which you could latch on any drug—consider it [to be] like a golf ball with very shallow ridges. Researchers were unable to really bring new drugs, which could block this. Now, what Revolution Medicine did was a totally new concept where they took advantage of another protein, which is called cyclophilin A, and the drug RMC-6236, or daraxonrasib, first binds to cyclophilin A. Then this bicomplex forms a tricomplex with RAS, and that's how it blocks it.

Initially, when this drug was built and developed, we were not very sure about its potency and activity because we know that pancreatic cancer is notoriously tough to treat. There is a stroma which surrounds the tumors; it's hard to penetrate. However, to our surprise, this drug really worked well. It showed remarkable overall survival of more than 13 months in second line, which is in patients who have already failed chemotherapy once. To see such activity in pancreatic cancer is remarkable. We have not seen such a thing in the last…20 years in the pancreatic cancer space. This is definitely very exciting news.

References

1. Khan HY, Al Hallak MN, Bannoura SF, et al. Preclinical evaluation of a novel hyperbolic NAMPT inhibitor in combination with pan-RAS targeted therapies in pancreatic ductal adenocarcinoma. Presented at: 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Presentation 4579.
2. Bannoura SF, Khan HY, Uddin MH, et al. Novel PCNA inhibitor synergizes with KRAS-targeted therapies in pancreatic ductal adenocarcinoma. Presented at the 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Presentation 4580.
3. Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. News release. Revolution Medicines Inc. April 13, 2026. Accessed April 29, 2026. https://tinyurl.com/44t5vh5d