Researchers at Roswell Park Comprehensive Cancer Center identified a strategy to overcome treatment resistance in KRAS- and RAS-targeted cancer therapies by blocking specific cell-cycle regulators. The preclinical findings, led by Roswell Park faculty members Vishnu Kumarasamy, PhD, Agnieszka Witkiewicz, MD, and Erik Knudsen, PhD, appeared in Cancer Research.
Cell-Cycle Vulnerability in Resistant Tumors
Targeted therapies against KRAS and RAS altered options for pancreatic, lung, and other malignancies. Their effectiveness stalls when tumors develop resistance and resume growth. To investigate how this resistance arises, the Roswell Park research team utilized transcriptomic, proteomic, and functional analyses across multiple cancer models. Drug therapies successfully block RAS signaling. Cancer cells sustain proliferation by activating alternative pathways. Persistent cell-cycle activity is a common feature of resistant tumors.
Inhibiting key cell-cycle regulators—specifically CDK4/6 or CDK2 kinases—restores cancer cell sensitivity to KRAS- and RAS-targeted drugs. These combination approaches yielded more durable tumor control than RAS inhibition alone in laboratory and animal models.
The FDA approval of the RAS inhibitor daraxonrasib marks an important advance in cancer treatment, but acquired resistance remains a major challenge,
said first author Vishnu Kumarasamy, PhD, Research Assistant Professor of Oncology in the Department of Molecular & Cellular Biology at Roswell Park. Our findings show that sustained cell cycle represents a common vulnerability that can be therapeutically exploited to overcome resistance and improve treatment durability.
Combination Strategies Extend KRAS Drug Effectiveness
Combination strategies guide future clinical approaches. They aim to extend the effectiveness of KRAS-targeted medicines and delay disease progression.
By co-targeting critical cell-cycle regulators,
added co-senior author Agnieszka Witkiewicz, MD, Professor of Oncology and Personalized Medicine in the Department of Molecular and Cellular Biology, we may be able to create more durable responses and overcome an important mechanism of drug resistance.
The study received support from the Roswell Park Alliance Foundation. It was backed by grants from the National Cancer Institute under project numbers R01CA275081 and P30CA016056, which is the NCI’s Cancer Center Support Grant to Roswell Park.
About Roswell Park Comprehensive Cancer Center
Roswell Park Comprehensive Cancer Center generates innovations that change how cancer is detected and treated. Individuals seeking further details regarding the center or the Roswell Park Care Network can visit www.roswellpark.org, call 1-800-ROSWELL (1-800-767-9355) or email ASKRoswell@RoswellPark.org.