Combining CDK4/6 Inhibitors and Senolytic Therapies Offers New Hope for Advanced Prostate Cancer Treatment

Prostate cancer remains a significant health challenge worldwide, with approximately 1.5 million new cases and nearly 397,000 deaths reported in 2022. It is the second most common cancer among men and a leading cause of cancer-related mortality. The primary treatment for metastatic prostate cancer (mPC) involves hormone therapy targeting androgen receptor signaling (ARPi). However, resistance to these therapies often develops, necessitating the development of innovative strategies.

Recent research efforts by the Vall d'Hebron Institute of Oncology focus on overcoming drug resistance in prostate cancer. In particular, scientists are exploring the potential of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, which have shown promise in treating other cancers like estrogen receptor-positive breast cancer. Despite encouraging preclinical results, clinical trials involving CDK4/6 inhibitors—either alone or combined with other therapies—have yielded mixed outcomes in prostate cancer.

A groundbreaking preclinical study led by Dr. Joaquin Mateo has introduced a novel approach to tackle this challenge. Instead of solely examining the effects of CDK4/6 inhibitors on tumor growth, the research investigates the cellular changes these drugs induce. The study found that while CDK4/6 inhibitors effectively halt tumor growth and induce a senescent (dormant) state in cancer cells, a subset of these dormant cells can survive and later reactivate, causing recurrence.

The researchers discovered that combining CDK4/6 inhibitors with senolytic therapies—drugs that specifically target senescent cells—can prevent tumor relapse. Furthermore, residual tumor cells demonstrated increased sensitivity to PARP inhibitors (PARPi), a class of drugs already approved for prostate cancer. This insight paves the way for sequential treatment strategies that involve administering CDK4/6 inhibitors, followed by senolytics or PARPi, to enhance therapeutic efficacy.

Another significant finding was that upon abrupt withdrawal of CDK4/6 inhibitors, tumor cells rapidly accrue DNA damage, creating opportunities for PARP inhibitor treatment. Sequential use—starting with CDK4/6 inhibition and then switching to PARP inhibition—resulted in pronounced anti-tumor activity, unlike simultaneous administration.

These advances highlight the potential of implementing a sequential treatment approach with CDK4/6 inhibitors, senolytics, and PARP inhibitors, offering promising new avenues in managing drug-resistant metastatic prostate cancer. This strategy could significantly improve patient outcomes and aid in designing future clinical trials aimed at personalizing prostate cancer therapy.

Source: https://medicalxpress.com/news/2025-07-cdk46-inhibitor-combination-drug-resistance.html