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A potent new combination therapy is showing remarkable promise in the fight against breast cancer, even in cases were tumors have become resistant to standard treatments. Researchers at The University of texas MD Anderson Cancer Center have discovered that pairing existing CDK4/6 inhibitors with a next-generation CDK2 inhibitor can deliver lasting tumor control across multiple subtypes of the disease-a notable step toward overcoming one of cancer’s most frustrating challenges.
Overcoming Resistance: A New Approach to Breast Cancer Treatment
A new study reveals a strategy to combat drug resistance in breast cancer by concurrently targeting two key cell cycle regulators.
- CDK4/6 inhibitors are currently the first-line treatment for hormone receptor-positive, HER2-negative metastatic breast cancer, but resistance inevitably develops.
- the combination of a CDK2 inhibitor (BLU-222) with CDK4/6 inhibitors produced strong and lasting anti-tumor effects in preclinical models.
- This approach restores the cancer cells’ natural braking system, halting cell proliferation and potentially stimulating an immune response.
- The findings suggest a clear path forward for clinical trials of next-generation CDK2 inhibitors in patients with resistant disease.
For patients with hormone receptor-positive, HER2-negative metastatic breast cancer, CDK4/6 inhibitors, when combined with endocrine therapy, have become a cornerstone of treatment. However, the initial benefits ofen fade as cancer cells develop resistance. The situation is even more challenging in triple-negative breast cancer, an aggressive form of the disease with limited targeted therapy options. Could blocking another pathway hold the key to preventing cancer cells from evading treatment?
Researchers, lead by Dr. Linjie Luo, MD, and Dr. Khandan Keyomarsi,explored this question,focusing on the combination of the selective CDK2 inhibitor BLU-222 with existing CDK4/6 inhibitors. Their work, published in Nature Scientific Reports on February 18, 2025, demonstrated a striking synergy.
Across all preclinical models tested-including those with treatment-resistant hormone receptor-positive disease and aggressive triple-negative breast cancer-the combination yielded robust and sustained anti-tumor effects. “This is an critically important and highly consistent finding,” said Dr. Keyomarsi. “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.”
Why Focus on CDK2?
Cancer cells rely on cyclin-dependent kinases (CDKs) to divide and replicate their DNA. While CDK4/6 inhibitors disrupt one part of this process, many cancers adapt by shifting their dependence to CDK2, allowing them to continue growing despite treatment.In essence, CDK2 becomes a backup plan for cancer cells.
The study demonstrates that inhibiting CDK2 effectively shuts down