CDK4/6 inhibitor combination could overcome drug resistance in advanced prostate cancer

With an estimated 1.5 million new cases and 397,000 deaths worldwide, prostate cancer is the world’s second most frequent cancer and the fifth leading cause of cancer death among men in 2022. Hormone therapy based on the inhibition of androgen receptor signaling (ARPi) is the mainstay of treatment for metastatic prostate cancer (mPC). However, cancer drug resistance ultimately arises, highlighting the need for more effective therapeutic strategies.

Aimed at overcoming drug resistance in prostate cancer treatment, one of VHIO’s Prostate Cancer Group key objectives is to advance insights into the genomic landscape and biology underpinning prostate cancer to expose novel vulnerabilities in tumor cells, develop new therapies, and optimize existing ones.

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors constitute a promising therapeutic avenue for different tumor types, some of which have already been approved for the treatment of advanced estrogen receptor (ER)-positive breast cancer. Despite promising results in preclinical models of mPC, particularly in studies combining them with other therapies, several clinical trials of CDK4/6i, as monotherapy or in combination, have generated negative results.

An innovative preclinical study led by Joaquin Mateo was designed to address the challenge of drug resistance associated with CDK4/6i in mPC from a new perspective. Instead of focusing solely on the direct effects of these drugs, they delved deeper into the changes in tumor cells induced by CDK4/6 inhibitors and thus sought to identify new therapeutic vulnerabilities.

An innovative sequential approach

Published in Molecular Cancer Therapeutics, the results of this study show that following treatment with CDK4/6 inhibitors, a small subset of persistent tumor cells enter a hibernation-like state, called “dormancy,” to evade therapy. These dormant cancer cells can unfortunately “wake up” years later, causing tumor relapse. The investigators showed that the combination of these inhibitors with senolytic therapies could prevent disease recurrence.

“In a range of in vitro and in vivo prostate cancer models, including patient-derived xenografts, our preclinical investigations show that CDK4/6 inhibitors halt the growth of prostate cancer cells and induce a senescent state, that can be targeted using senolytic therapies,” said Joaquin Mateo, a Medical Oncologist at the Vall d’Hebron University Hospital, co-leader of VHIO’s Prostate Cancer Group, and corresponding author of this study.

The researchers also reported that residual tumor cells show increased sensitivity to PARPi, a type of targeted cancer drug already approved for the treatment of prostate cancer. This observation opens the door to designing new sequential treatment strategies that combine both therapies to improve clinical outcomes.

Notably, in a second phase of their preclinical investigations, this sequential strategy also capitalizes on a second biological effect of CDK4/6 inhibitors on tumor cells, observing that when exposure to these drugs stop abruptly, tumor cells rapidly accumulate DNA damage.

“This effect opens a window of opportunity for treatment with PARP inhibitors. Upfront combined inhibition with CDK4/6 and PARP1 has no antitumor effect. However, their sequential use adding PARPi upon CDK4/6i withdrawal results in striking antitumor activity,” observed Julian Brandariz, a Ph.D. Student of VHIO’s Prostate Cancer Group and first author of this work.

“Our results demonstrate the potential of CDK4/6i in prostate cancer therapy, particularly when followed by sequential treatment with senolytic therapy or PARPi. This new one-two punch strategy holds promise in overcoming cancer drug resistance, improving treatment outcomes for metastatic prostate cancer, and open avenues for repurposing CDK4/6i therapy in metastatic prostate cancer,” concluded Mateo.

These findings represent a step forward in personalizing and optimizing therapy for advanced prostate cancer and could provide new scientific rationale for the design of future clinical trials.