Andreas Varkaris, MD, PhD

Ioannis Sanidas, PhD

Dejan Juric, MD

A critical challenge in treating hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer is that nearly all patients eventually develop resistance to the current standard of care, CDK4/6 inhibitors. However, a solution may be on the horizon in the form of a newer class of drugs that selectively target a related protein, CDK2.

In a recent study led by Dejan Juric, MD, and supervised by Ioannis Sanidas, PhD, and Andreas Varkaris, MD, PhD, of the Mass General Brigham Cancer Institute, researchers aimed to better understand how CDK2 inhibitors work and which patients might benefit most.

They found that CDK2 inhibitors attack cancer cells differently than existing CDK4/6 inhibitors. Rather than blocking entry into the cell cycle—or the cell’s decision to start proliferating—CDK2 inhibitors slow DNA replication, increase DNA damage and prevent cells from successfully completing cell division.

Resistant cancer cells appear to shift their dependence from CDK4/6 to CDK2, making them more vulnerable to CDK2 inhibition. The team also found evidence that CDK2 inhibitors work through a different mechanism than expected, one that’s independent of the retinoblastoma tumor suppressor, a key protein regulator of cell proliferation.

Finally, analysis of samples from an early CDK2 inhibitor trial suggested that tumors retaining a non-mutated TP53 gene may be more likely to benefit from treatment, pointing to a potential biomarker for patient selection.

Overall, the study provides encouraging evidence that CDK2 inhibitors may someday be a therapeutic option for patients whose breast cancers no longer respond to the current standard of care, potentially even in combination with CDK4/6 inhibitors.

Published in Cancer Research on July 20, 2026 | Read the paper: “CDK2 Inhibition Exerts RB-Independent Antitumor Activity in CDK4/6 Inhibitor–Resistant HR+/HER2− Breast Cancer”

Summary reviewed by: Ioannis Sanidas, PhD, co-senior author