New mechanisms of resistance called lineage plasticity in cancer

June 22, 2021

While patient survival has been extended by modern drugs that block the production or action of male hormones that fuel prostate cancer — androgen receptor inhibitors such as enzalutamide, apalutamide, darolutamide, and abiraterone — eventually these drugs stop working. At that point, a patient’s disease is considered incurable, or what doctors call metastatic, castration-resistant prostate cancer.

In a new study, a team of researchers led by Joshi Alumkal, MD, who leads the prostate and genitourinary medical oncology section at the University of Michigan Rogel Cancer Center, uncovered new mechanisms underlying an important type of resistance called lineage plasticity. That’s when castration-resistant prostate cancers undergo a deadly identity switch — shifting from resembling glandular cells to neuroendocrine cells, which can behave more like small cell lung cancer.

The findings using human and mouse cell models and tissue biopsies from patients appear in Clinical Cancer Research and outline a promising path to overcoming this form of resistance: BET bromodomain inhibitors. These compounds work against bromodomain and extra-terminal (BET) proteins, which are involved in regulating gene activation.

Patients diagnosed with treatment-emergent neuroendocrine prostate cancer fare much worse than patients whose tumors remain adenocarcinomas — glandular tumors — surviving for only about one-third as long. Furthermore, there are very limited treatment options for patients with treatment-emergent neuroendocrine prostate cancer.

This line of investigation began when Alumkal was at the Knight Cancer Institute at Oregon Health & Science University and continued after his move to the U-M in 2019.

The major question the researchers sought to answer was whether modern prostate cancer drugs — the new and more potent androgen receptor inhibitors — might be so effective in shutting down the androgen receptor in some tumors that these drugs could actually promote the tumors’ switch to become neuroendocrine tumors.

And the answer appears to be yes.

Through 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 research team found that androgen receptor inhibition was accentuating a neuroendocrine prostate cancer lineage plasticity program in the resistant cells — an effect not achievable in the sensitive cells.

And it was this work to uncover the mechanisms giving rise to treatment-emergent neuroendocrine cancer that also pointed toward a potential solution: BET inhibitors.

Though E2F1 is not targetable directly, Alumkal’s team determined that E2F1 cooperates with BET bromodomain proteins to turn on a neuroendocrine prostate cancer lineage plasticity program. Blocking BET bromodomain proteins in cell models stopped the activation of this program that drives the development of neuroendocrine prostate tumors, the research team found.

“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.

The study builds on a previous clinical trial by Alumkal and colleagues, which found 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. Additionally, 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, suggesting the most aggressive tumors may be particularly susceptible to BET bromodomain inhibition.

Visit University of Michigan for more news