New Strategies in Breast Cancer Treatment: Overcoming Resistance to CDK Inhibitors

In a recent presentation, Shom Goel, MBBS, FRACP, PhD, highlighted the evolving landscape of breast cancer therapy, focusing on innovative approaches to tackle resistance in hormone receptor (HR)-positive/HER2-negative breast cancer. He emphasized the pivotal role of CDK4/6 inhibitors in first-line treatment, advocating for their use as early as possible to maximize the suppression of cell-cycle genes and delay cancer cells’ ability to develop resistance. He emphasized the use of letrozole plus CDK4/6 inhibitors, highlighting palbociclib, ribociclib, and abemaciclib. For patients who develop CDK4/6 resistance, newer classes of CDK inhibitors that work on the same part of the cell cycle as CDK4/6 agents show potential.

CDK2 inhibitors are emerging as a promising strategy. “CDK2 inhibitors effectively shut down an escape route for cancer cells, restoring tumor control,” Dr Goel remarked. However, he noted that the toxicity profile of CDK2 inhibitors remains unclear, with early data showing varying side effects such as gastrointestinal and hematologic toxicities.

Dr Goel also touched on CDK7 inhibitors, which target multiple pathways in cancer cells, including estrogen receptor signaling and cell cycle activity. Early studies suggest a potential benefit, but significant gastrointestinal toxicities pose challenges.

Another exciting area of development involves KAT6 inhibitors. Tumors with high KAT6 expression are more dependent on this protein for survival, making it a promising target. Pfizer’s KAT6 inhibitor program has shown that cells with luminal gene expression are more sensitive to this therapy than basal-type cells. The KATSIS-1 trial, the only randomized study in the post – CDK4/6 inhibitor setting, is now underway. While preliminary data are encouraging, issues such as taste disturbances and cytopenias remain the biggest challenges.

These advancements underscore the need for innovative strategies to overcome resistance while balancing efficacy and tolerability in breast cancer treatment.

Source: Goel SB. Emerging agents to overcome CDK4/6 inhibitor resistance. Presented at: San Antonio Breast Cancer Symposium 2025. December 9, 2025; San Antonio, TX. Presentation ED1-03.