In a preclinical study published recently in Cancer Research, investigators identified a strategy that may help guide future clinical strategies for overcoming treatment resistance associated with KRAS-targeted cancer therapies. This preclinical study was led by Roswell Park Comprehensive Cancer Center faculty members Vishnu Kumarasamy, PhD, Agnieszka Witkiewicz, MD, and Erik Knudsen, PhD.
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 team used transcriptomic, proteomic, and functional analyses in multiple cancer models. They 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,” said first study author Dr. Kumarasamy, Research Assistant Professor of Oncology in the Department of Molecular & Cellular Biology. “Our findings show that sustained cell cycle represents a common vulnerability that can be therapeutically exploited to overcome resistance and improve treatment durability.”
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,” added co-senior author Dr. Witkiewicz, Professor of Oncology and Personalized Medicine in the Department of Molecular and Cellular Biology.
DISCLOSURE: The research was funded in part by the Roswell Park Alliance Foundation and by grants from the National Cancer Institute. For full disclosures of the study authors, visit aacrjournals.org/cancerres.
