New strategy identified for overcoming resistance to KRAS-targeted cancer therapies

Researchers at Roswell Park Comprehensive Cancer Center have identified a promising strategy for overcoming one of the biggest challenges facing KRAS-targeted cancer therapies: treatment resistance. Results of the preclinical study, led by Roswell Park faculty members Vishnu Kumarasamy, PhD, Agnieszka Witkiewicz, MD, and Erik Knudsen, PhD, were recently published in Cancer Research, a journal of the American Association for Cancer Research (AACR). 

Targeted therapies against KRAS and RAS have transformed the treatment landscape for patients with pancreatic, lung, and other cancers. However, their benefits can be limited when cancer cells develop resistance and tumors begin to grow again. To better understand how that resistance develops, the Roswell Park team used transcriptomic, proteomic and functional analyses in multiple cancer models. The researchers found that even when RAS signaling was successfully blocked, cancer cells could maintain cell proliferation by activating alternative pathways. Persistent cell-cycle activity emerged as a common feature of resistant tumors. 

The team then demonstrated that blocking the key cell-cycle regulators CDK4/6 or CDK2 kinases, restored sensitivity to KRAS- and RAS-targeted therapies. Combination approaches produced more durable tumor control in laboratory and animal models than KRAS inhibition alone. 

The FDA approval of the RAS inhibitor daraxonrasib marks an important advance in cancer treatment, but acquired resistance remains a major challenge. Our findings show that sustained cell cycle represents a common vulnerability that can be therapeutically exploited to overcome resistance and improve treatment durability."

Vishnu Kumarasamy, PhD, first author, Research Assistant Professor of Oncology, Department of Molecular & Cellular Biology

The findings may help guide future clinical strategies aimed at extending the effectiveness of KRAS-targeted medicines and delaying disease progression. "By co-targeting critical cell-cycle regulators, we may be able to create more durable responses and overcome an important mechanism of drug resistance" adds co-Senior Author Agnieszka Witkiewicz, MD, Professor of Oncology and Personalized Medicine in the Department of Molecular and Cellular Biology.

The research was funded in part by the Roswell Park Alliance Foundation and by grants from the National Cancer Institute (project numbers R01CA275081 and P30CA016056, the NCI's Cancer Center Support Grant to Roswell Park).