Roswell Park-Led Team Proposes CDK2 Enzyme as New Target for Cancer Therapy

An enzyme called cyclin-dependent kinase 2 (CDK2) regulates the cell cycle and may have the potential to drive therapeutic resistance to common breast cancer drugs — including a class of targeted treatments known as CDK4/6 inhibitors. A new study led by Agnieszka Witkiewicz, MD, and Erik Knudsen, PhD, of Roswell Park Comprehensive Cancer Center and colleagues highlights the therapeutic impact of CDK2 inhibitors and is published in the journal Nature Communications.

FDA-approved CDK4/6 inhibitors include abemaciclib (brand name Verzenio), ribociclib (brand name Kisqali) and palbociclib (brand name Ibrance), all of which can be used in combination with hormone therapy to treat hormone receptor-positive breast cancers. However, the disease can become resistant to those treatments, often due to the activation of CDK2.

The preclinical research study led by investigators at Roswell Park and the University of California Santa Cruz, in collaboration with Incyclix Bio Inc., revealed that some tumors are exceptionally dependent on CDK2 and are vulnerable to a CDK2 inhibitor called INX-315, a drug candidate developed by Incyclix Bio. The research team found that several key biomarkers can predict sensitivity to CDK2 in preclinical models, and those biomarkers could help identify patients who are most likely to respond to CKD2-targeted therapies.

“We found that pharmacologically targeting a single kinase, CDK2, can trigger two distinct cellular responses depending on the tumor type,” says Vishnu Kumarasamy, PhD, first author on the new study and a Research Assistant Professor of Oncology in Roswell Park’s Department of Molecular & Cellular Biology.

The team also found that a broader range of tumors, including both breast and pancreatic cancer models, respond to CDK2 inhibitors in a complex process that can hamper the ability of tumor cells to divide. The researchers identified ways of combining treatments to strengthen that response in order to effectively limit tumor growth.

“We hope these findings with CDK2 inhibitors in preclinical models will be translated into new clinical trials to help breast cancer patients whose disease has progressed on CDK4/6 inhibitors — and provide new opportunities in multiple additional cancers,” says Dr. Witkiewicz, Director of the Advanced Tissue Imaging Shared Resource at Roswell Park and co-corresponding author of the study.

Incyclix officials suggest that combining INX-315 with CDK4/6 inhibitors could be a promising way to extend the use of INX-315 to treat tumors other than those dependent on CDK2.

“By leveraging cell cycle biomarkers, we hope to be able to identify patients that will benefit most from combination treatments,” says Patrick Roberts, PharmD, PhD, Chief Executive Officer and Co-Founder of Incyclix Bio. “These striking new findings validate the combination of INX-315 with CDK4/6 inhibitors as a promising therapeutic strategy with potential application beyond patients with CDK2-addicted cancers.”

INX-315, the CDK2 inhibitor used in the study, was provided by Incyclix Bio.

This work was supported by grants awarded by the National Institutes of Health and National Cancer Institute (CA267467, CA247362, CA275081 and P30CA016056), and used several Roswell Park core research resources.