Study identifies a powerful strategy to overcome drug resistance in breast cancer

A new preclinical study from researchers at The University of Texas MD Anderson Cancer Center, published today in Nature Communications, identifies a powerful strategy to overcome drug resistance in breast cancer by simultaneously targeting two key cell-cycle regulators, CDK2 and CDK4/6. CDK4/6 inhibitors, combined with endocrine therapy, are the standard first-line treatment for hormone receptor (HR)-positive, HER2-negative (HR+/HER2−) metastatic breast cancer, but resistance inevitably develops over time. In triple-negative breast cancer (TNBC) – an aggressive subtype with limited targeted treatment options – the benefit of CDK4/6 inhibitors remains unclear.

Seeking to address both of these challenges, researchers led by postdoctoral fellow Linjie Luo, M.D., Ph.D., and Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, found that combining the selective CDK2 inhibitor BLU-222 with CDK4/6 inhibitors produces strong, durable anti-tumor effects. These effects were conmd ansistent across every preclinical model of breast cancer tested, including treatment-resistant and aggressive TNBC. Notably, this synergy was observed without exception, underscoring the broad translational potential of the approach.

This is an important and highly consistent finding. Across all resistant HR-positive models and all TNBC models we tested, the combination of BLU-222 with CDK4/6 inhibitors consistently outperformed standard-of-care therapies, producing durable tumor regression and prolonged survival."

Khandan Keyomarsi, Ph.D., Professor of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center

Why did the researchers target CDK2?

Cancer cells divide rapidly, relying on proteins called cyclin-dependent kinases (CDKs) to do so. CDK proteins control cell division and DNA replication, and many breast cancers become especially dependent on CDK2, CDK4 and CDK6 to survive.

While CDK4/6 inhibitors block part of this process, cancer cells often adapt by shifting their dependence to CDK2, allowing them to survive despite treatment. This study shows that targeting CDK2 effectively shuts down this escape route.

Although CDK2 has long been recognized as an important cancer driver, earlier CDK2 inhibitors were limited by toxicity. Newer and more selective drugs, such as BLU-222, now have made CDK2 inhibition a realistic and promising therapeutic strategy.

How does this combination treatment strategy work?

BLU-222, alone or combined with CDK4/6 inhibitors, triggered the cancer cells' own natural "brakes" on cell division by increasing levels of two proteins, p21 and p27. These proteins normally help keep cell growth under control but are often suppressed in drug-resistant tumors.

Restoring p21 and p27 blocked both CDK2 and CDK4 activity, effectively shutting down the cancer cells' ability to continue dividing. Importantly, when researchers genetically removed p21 or p27 using CRISPR, the powerful synergy of the drug combination disappeared, proving these proteins are essential to the treatment's success.

RNA sequencing further revealed that the combination therapy activated cellular senescence (a permanent shutdown of cancer cell growth) and interferon signaling, which may help stimulate immune responses and explain why tumor regressions were so durable.

What impact does this have on future therapies for drug-resistant breast cancer?

According to Keyomarsi, an important aspect of this study is that it arrives at a time when multiple next-generation CDK2 inhibitors are making their way through the pipeline and into clinical trials. This trial shows strong preclinical evidence for the approach.

"Our data demonstrate that targeting CDK2 is not just additive – it fundamentally restores control over the cell cycle in resistant tumors. Therefore, this study provides a clear blueprint for how these drugs should be used clinically," Keyomarsi said. "This is significant because there is an urgent unmet clinical need for patients with CDK4/6 inhibitor-resistant HR-positive breast cancer and for those with triple-negative disease."