BET Inhibitors May Be Effective In Preventing Certain Types of Prostate Cancer Drug Resistance

According to the study, lineage plasticity—the shift in castration-resistant prostate cancers from resembling glandular cells to neuroendocrine cells—may potentially be overcome through the use of bromodomain and extra-terminal (BET) protein inhibitors.

New mechanisms responsible for a critical type of prostate cancer drug-resistance have been uncovered by a study published in Clinical Cancer Research. According to the study, lineage plasticity—the shift in castration-resistant prostate cancers from resembling glandular cells to neuroendocrine cells—may potentially be overcome through the use of bromodomain and extra-terminal (BET) protein inhibitors.

“We know that treatment-emergent neuroendocrine prostate cancer is becoming more frequent as we use more newer and more potent androgen receptor inhibitors,” said Joshi Alumkal, MD, in a press release. “Our prior work examining patients progressing on these newer androgen receptor inhibitors demonstrated that neuroendocrine prostate cancer was found in 17% of cases. By comparison, we find it in less than 1% of patients who have not undergone any form of androgen receptor inhibition. This strongly suggests that interference with androgen receptor function contributes to the increased numbers of treatment-emergent neuroendocrine prostate cancers we now see clinically.”

Patients with a treatment-emergent neuroendocrine prostate cancer diagnosis have significantly worse outcomes than patients whose tumors remain adenocarcinomas, surviving only one-third as long. Treatment options for these patients are limited, and metastatic, castration-resistant prostate cancer is considered incurable.

The current study sought to answer whether modern prostate cancer drugs were so effective in shutting down the androgen receptor in certain tumors that they could actually promote the tumors' switch to neuroendocrine tumors. By conducting a series of experiments using laboratory cell models that were either sensitive to newer androgen receptor inhibitors or their counterpart cell models with acquired resistance, the investigators determined that androgen receptor inhibition was accentuating a neuroendocrine prostate cancer lineage plasticity program in the resistant cells. This effect was not achievable in the sensitive cells.

“Ultimately, we found that a critical difference that may allow the resistant cells to react differently and become more neuroendocrine is due to the way their DNA is organized and packaged,” Alumkal said in the press release. “In the treatment-resistant cells, the chromatin is organized in a way that's more conducive to turning on that neuroendocrine program when the androgen receptor is blocked. It is as though the resistant cells have evolved to develop a rabbit hole through which they can change their identity and escape androgen receptor inhibition. We also found that high levels of a transcription factor called E2F1, which is involved in stemness and cell differentiation, is important for the resistant cells' ability to switch identities.”

E2F1 is not targetable directly, but the researchers found that E2F1 cooperates with BET bromodomain proteins to turn on a neuroendocrine prostate cancer lineage plasticity program. According to the investigators, blocking BET bromodomain proteins in cell models prevented the program that drives the development of neuroendocrine prostate tumors from activating.

“When we treated a variety of treatment-emergent neuroendocrine prostate cancer cell lines with BET inhibitors, we greatly reduced the viability of these tumors, including tumors derived from patients,” Alumkal said in the release.

The current study builds off of prior research conducted by the same team, which found that a BET bromodomain inhibitor compound developed by Zenith Epigenetics, ZEN-3694, looked most active in castration-resistant prostate tumors from patients who had the lowest androgen receptor activity. Further, patients in the trial whose tumors didn't respond well to androgen receptor inhibitors prior to study enrollment appeared to have the most durable control with ZEN-3694, which suggested the most aggressive tumors may be particularly susceptible to BET bromodomain inhibition. A larger, international, randomized clinical trial is planned to evaluate the effectiveness of ZEN-3694 with a particular focus on men whose tumors may be less dependent on the androgen receptor.

The study authors said the research points toward BET bromodomain inhibitors as potentially most beneficial for patients whose prostate cancer is no longer as dependent on the androgen receptor, and those with subsets of treatment-emergent neuroendocrine prostate cancer, particularly tumors in which transcription factor E2F1 may be playing an important role.

REFERENCE

Overcoming a newly recognized form of resistance to modern prostate cancer drugs [news release]. EurekAlert; June 18, 2021. Accessed June 21, 2021. https://www.eurekalert.org/pub_releases/2021-06/mm-u-oan061821.php