Drug pair slows resistant prostate tumors in mice

In the University of Michigan lab, researchers studied prostate cancer cells lacking two genes linked to treatment resistance: TP53 and RB1. The researchers found that the cells were doing two things at once—turning off glandular genes and activating programs associated with stem cells. That identity switch, called transdifferentiation, can emerge after androgen receptor inhibitors stop controlling advanced disease.

The team had already tested BET bromodomain inhibitors, a drug class that blocks pathways involved in activating alternate cell-identity programs. The drugs slowed prostate cancer cell lines but did not kill them. Researchers then added DNMT inhibitors, which can turn genes back on, including glandular genes often lost during transdifferentiation.

The pairing worked better than either treatment alone. It suppressed the growth of prostate cancer cell lines and produced the same result in tumors implanted in mice. The researchers also reported that the combination reversed a significant portion of the tumors’ gene-expression changes and reduced tumor growth at doses lower than the recommended dose; the mice tolerated the treatment well. DNMT inhibitors are already approved by the Food and Drug Administration for other conditions, including blood cancers, but this combination remains untested in patients.

So what changes in practice? Not treatment today, but a possible route for patients whose tumors have escaped hormone-targeting drugs by changing identity. A clinical trial would still need to show that the combination is safe and effective in people, while biomarkers could help identify which patients are most likely to benefit.

Joshi Alumkal and Will Storck’s team now wants to pinpoint the genes driving the antitumor effect and determine whether transdifferentiation can be blocked before it begins. The researchers hope to develop clinical trials in transdifferentiated prostate cancer and investigate whether the strategy could apply to similar identity changes in lung and pancreatic cancers.