Commonly used prostate cancer treatment rewires engine of prostate tumors: Research

Drugs like enzalutamide that inhibit male hormones from activating the androgen receptor have been used to treat advanced prostate cancer for more than a decade. A new study from the University of Michigan Rogel Cancer Center suggests androgen receptor inhibitors can fundamentally rewire and reshape how prostate tumors function, and in certain cases even make them more aggressive. These findings have been published in Nature Communications.

Male hormones function as fuel, turning on the androgen receptor that acts as the engine of prostate cancer cells. The researchers wanted to understand what was present in these tumors, to begin with and what happened after tumors started to grow on enzalutamide treatment. They recruited patients to a longitudinal study to obtain metastatic biopsies before enzalutamide treatment and at the time the tumor became resistant to treatment. His team collected serial biopsies from 21 patients, enabling them to understand the workarounds in the tumor from each patient.

When they compared the baseline sample to the progression sample from the same patient, most tumors showed no significant gene expression changes.In three of the 21 cases, the team saw a profound shift in the wiring—or gene expression program—of the tumors.

But they found that in 15 percent of cases, the tumors also became fuel-independent for another reason.Also three tumors converted to become double negative prostate cancer—akin to an electric vehicle.Although the baseline tumors appeared similar under the microscope, the research team identified specific genes that were highly expressed in those that eventually became double negative prostate cancer.

This result suggests that certain tumors exist in a hybrid state, initially dependent on fuel but at risk for becoming a fuel-independent double negative prostate cancer during enzalutamide treatment.

Reference:

Joshi Alumkal et al,Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity,Nature Communications,DOI 10.1038/s41467-022-32701-6