Study Finds Way to Overcome KRAS Drug Resistance

Roswell Park researchers report that blocking CDK4/6 or CDK2 kinases restored sensitivity to KRAS- and RAS-targeted therapies in preclinical models.

Updated on Nov. 3, 2026 in Cancer

Bold flat-color editorial illustration of a clear cell-culture flask with amber liquid on a laboratory bench, evoking drug-resistance research in cancer treatment. — Researchers at Roswell Park Comprehensive Cancer Center report that blocking CDK4/6 or CDK2 kinases restored sensitivity to KRAS-targeted cancer drugs in preclinical models. AI Illustration. Upload story photo >

Researchers at Roswell Park Comprehensive Cancer Center published a preclinical study in Cancer Research identifying a strategy to overcome resistance to KRAS-targeted cancer therapies. Blocking CDK4/6 or CDK2 kinases restored sensitivity to these treatments in laboratory and animal models.

Why it matters

Targeted therapies against KRAS and RAS have transformed treatment for patients with pancreatic, lung, and other cancers, but tumors often develop resistance. The findings suggest combination approaches may extend how long these medicines remain effective.

The study was conducted in multiple cancer models using transcriptomic, proteomic, and functional analyses, with combination testing in laboratory and animal settings. Human clinical efficacy of CDK4/6 or CDK2 co-blockade alongside KRAS-targeted therapy has not been reported in the extraction.

The players

Roswell Park Comprehensive Cancer Center

A Buffalo-based National Cancer Institute-designated center that conducted the study on KRAS and RAS therapy resistance.

Erik Knudsen

A Roswell Park faculty member who co-led the study on cell-cycle regulators and resistance to KRAS- and RAS-targeted therapies.

The details

The team, led by Vishnu Kumarasamy, Agnieszka Witkiewicz, and Erik Knudsen, found that when RAS signaling was blocked, cancer cells kept proliferating by activating alternative pathways. Persistent cell-cycle activity emerged as a common feature of resistant tumors, and blocking CDK4/6 or CDK2 kinases restored sensitivity to treatment.

Article reporting the preclinical study was published on November 3, 2026.

Big Picture

The FDA's approval of the RAS inhibitor daraxonrasib marks a milestone for RAS-directed cancer treatment. This research addresses the next challenge by showing how tumors evade such drugs and how combination strategies might sustain their effect.

For patients with KRAS-driven pancreatic or lung cancers, this research points toward future combination treatments that could extend the benefit of current targeted drugs. Any such approach would require clinical trials before it reaches routine care, so current treatment decisions remain with patients and their oncologists.

The takeaway

Overcoming drug resistance may depend on blocking the cell-cycle pathways that tumors use to survive targeted therapy. Patients should discuss any emerging combination options with their oncology team as they move from laboratory research toward clinical testing.