Daraxonrasib Nearly Doubles Survival in Advanced Pancreatic Cancer

Survival rates for patients with advanced pancreatic cancer jumped from 6.7 months to 13.2 months in a large clinical trial evaluating the experimental drug daraxonrasib. This result, presented at the American Society of Clinical Oncology annual meeting and published in the New England Journal of Medicine, marks a significant shift in treating one of the most stubborn oncological targets.

Disarming the RAS protein family

RAS proteins act as molecular on-off switches for cell growth and division, but mutations frequently lock them in the 'on' position, driving uncontrolled tumor proliferation. Historically, these proteins have been considered 'undruggable' because their surfaces lack the deep pockets required for conventional small-molecule drugs to anchor effectively. While the first anti-RAS drug approved in 2021 targeted a single mutation in the KRAS protein, it offered limited utility and faced rapid resistance issues.

Developed by Revolution Medicines, daraxonrasib breaks this pattern by switching off all three members of the RAS protein family. In a trial of 500 participants, the drug's ability to target multiple RAS proteins nearly doubled the median survival time compared to standard chemotherapy. Researchers like Kevan Shokat at the University of California, San Francisco, suggest that combining daraxonrasib with single-mutation KRAS inhibitors could further extend these clinical benefits.

Targeting the next generation of smooth proteins

Success with RAS is providing a blueprint for tackling other notoriously smooth protein targets, most notably MYC. Approximately 70% of all cancers are fueled by excessive MYC levels, yet the protein's lack of binding pockets makes drug design exceptionally difficult. Unlike the straightforward mutations seen in KRAS, MYC activity often stems from gene duplication or complex genetic changes rather than single-base substitutions.

Several experimental approaches are currently testing the limits of protein interference. Peptomyc is testing OMO-103, a 'mini protein' designed to disrupt MYC's interactions, while researchers at Oregon Health and Science University are utilizing artificial intelligence to identify compounds that bind to MYC's DNA-repair functions. At the Geisel School of Medicine at Dartmouth College, efforts are underway to find compounds that block MYC's ability to activate specific downstream genes.

This breakthrough with daraxonrasib proves that even the most structurally challenging protein families can be successfully targeted, setting the stage for a new era of precision oncology against MYC and p53.

Source: Landmark pancreatic cancer treatment paves way for targeting other tricky tumors
Domain: scientificamerican.com