Scientists at the Vall d’Hebron Institute of Oncology (VHIO) have made a significant preclinical breakthrough that could pave the way for improved treatment of metastatic prostate cancer.

In this study, they showed across various in vitro and in vivo prostate cancer models, including patient-derived xenografts, that prostate cancer cells develop a senescent phenotype following CDK4/6 inhibition, which can be specifically targeted with senolytic compounds.

CDK4/6 inhibitors, drugs that have revolutionized treatment in certain breast cancers, showed promise in early prostate cancer studies but failed to deliver substantial benefit in clinical trials, especially when used alone or alongside other drugs simultaneously. Focusing beyond immediate drug effects, the VHIO research team discovered a crucial biological shift in prostate cancer cells treated with CDK4/6 inhibitors: a subset of these cells enter a dormant, dormant-like state known as senescence, wherein they survive therapy by “hibernating.” These dormant cells can evade treatment and later cause cancer recurrence.

The team’s work revealed a two-fold opportunity. First, pairing CDK4/6 inhibitors with senolytic therapies,drugs designed to clear out these senescent cells, could significantly reduce relapses by eliminating cells that otherwise remain hidden during treatment. More strikingly, after the cessation of CDK4/6 inhibitor therapy, these dormant tumor cells become highly sensitive to PARP inhibitors, a class of targeted drugs already approved for certain prostate cancers. This sensitivity creates a critical “window of opportunity” during which PARP inhibitors can exert powerful antitumor effects.

Importantly, the study clarified that administering CDK4/6 inhibitors and PARP inhibitors at the same time does not achieve this benefit. Instead, sequencing the therapies—first using CDK4/6 inhibitors to induce dormancy and then applying PARP inhibitors after withdrawing the initial treatment—results in a pronounced “one-two punch” that delivers significantly improved tumor control. This approach exploits the period when tumor cells accumulate DNA damage following withdrawal of CDK4/6 inhibitors, making them particularly vulnerable to subsequent PARP inhibition.

These findings offer a paradigm shift in how combination therapies for metastatic prostate cancer might be designed, emphasizing timing and biological vulnerability over mere dosage or drug pairing. Not only does this provide a new lease on life for CDK4/6 inhibitors in prostate cancer, but it also opens the door for similar sequential treatment strategies in other cancers grappling with drug resistance.

Source.