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KRAS-targeted cancer therapies are powerful — but tumors often find a way around them. Roswell Park researchers may have found the workaround to the workaround: pairing KRAS inhibitors with cell-cycle blockers (CDK4/6 or CDK2 inhibitors) restored drug sensitivity and produced more durable tumor control in lab and animal models. The findings, published in Cancer Research, could shape future treatment strategies for pancreatic, lung, and other cancers.
KRAS-targeted therapies have been a game-changer for patients with pancreatic, lung, and other cancers — but resistance is a persistent challenge in oncology. Now, researchers at Roswell Park Comprehensive Cancer Center think they've found a way to fight back. Their preclinical study, published in Cancer Research, reveals that when RAS signaling is blocked, cancer cells don't simply stop — they reroute through alternative pathways to keep dividing, with persistent cell-cycle activity emerging as a hallmark of resistant tumors.
The Roswell Park team used transcriptomic, proteomic, and functional analyses across multiple cancer models to map out this resistance mechanism. Their solution? Target the cell cycle too. Blocking key regulators CDK4/6 or CDK2 kinases alongside KRAS inhibition restored drug sensitivity and delivered more durable tumor control than KRAS inhibition alone.
Key Takeaways:
Why it matters: With the FDA's recent approval of the RAS inhibitor daraxonrasib, acquired resistance is now a frontline clinical challenge. This research offers a mechanistically grounded strategy to extend the durability of KRAS-targeted therapies — potentially keeping more patients in remission, longer.
