Androgen deprivation therapy (ADT) is the principal treatment for metastatic prostate cancer, but progression to castration-resistant prostate cancer (CRPC) is nearly universal. In recent years, potent androgen receptor inhibitors (AR) have been developed, including the AR antagonist enzalutamide.
While successful in most cases, these drugs can eventually stop working, there is a limited understanding of how this change occurs. A new study from the University of Michigan Rogel Cancer Center suggests that androgen receptor inhibitors can fundamentally rewire and reshape prostate tumors function and, in certain cases, even make them more aggressive.
Joshi Alumkal, M.D., Wicha Family Professor of Oncology and Professor of Internal Medicine, whose team led this research in collaboration with the Zheng Xia laboratory at the Oregon Health & Sciences University Knight Cancer Institute, said, “The greatest unmet need in the clinic right now is understanding the workarounds in a tumor that becomes resistant to androgen receptor targeting drugs so we can determine how best to treat the patient whose tumor has begun to grow.”
“Once enzalutamide stops working, there are limited options. We don’t know how or why most tumors become resistant.”
Scientists wanted to comprehend what was present in these tumors to begin with, and what happened after tumors started to grow on enzalutamide treatment. Patients were enrolled in a long-term trial to collect metastatic biopsies before and after the tumor developed therapy resistance. Scientists obtained repeated samples from 21 patients, which allowed them to comprehend the mechanisms at play in each patient’s tumor.
Alumkal says, “this is the largest collection of matched metastatic biopsies before and after enzalutamide. To understand resistance to drugs, researchers often collect samples from some patients before treatment and from a different group whose tumors are treatment resistant. However, that approach is much less precise because there could be other significant differences between those patients. You can’t pinpoint if the differences have anything to do with drug exposure or have more to do with the tumors just being different, to begin with.”
The sequential sampling method offers a clearer picture of how enzalutamide resistance might emerge.
After comparison of the baseline sample to the progression sample from the same patient, scientists didn’t found significant gene expression changes in most tumors.
Alumkal says, “That the gene expression program of a tumor before treatment looked very similar at progression while on enzalutamide is quite remarkable. It speaks to how well most of the tumors could adapt and keep the androgen receptor engine on despite enzalutamide treatment.”
But that wasn’t the only surprise.
In three of the 21 cases, Alumkal and his team saw a profound shift in the tumors’ wiring—or gene expression program—.
Alumkal said, “We knew that sometimes tumors become fuel-independent and no longer rely on the androgen receptor. These tumors instead turn on a gene expression program more common in nerve cells, rather than prostate cells, and shift to an aggressive form called neuroendocrine prostate cancer.”
“In 15 percent of cases, the tumors also became fuel-independent for another reason. These tumors were wired uniquely and were most consistent with a subtype of prostate cancer called double-negative prostate cancer, meaning the tumors no longer had the androgen receptor as an engine. But they also did not become neuroendocrine prostate cancer.”
“Initially, nearly all prostate tumors are gas guzzlers: very fuel dependent and powered by the androgen receptor as the engine. When treated with hormonal treatments, most tumors remain fuel-dependent but become more fuel efficient, able to go farther with less gasoline.”
“Our work showed that the majority of the tumors—even after receiving enzalutamide—remain very fuel-dependent, which suggests that continuing to target the androgen receptor could make an enormous difference in these tumors.”
Alumkal found that three tumors converted into double negative prostate cancer—akin to an electric vehicle. The gasoline engine was replaced by a completely distinct set of machinery that allowed tumors to grow and survive. “The DNA mutations found in the baseline and progression biopsies from these converter tumors were the same, which strongly suggests that enzalutamide completely rewired the engine of the original fuel-dependent tumor to become fuel-independent at disease progression. It’s a dramatic shift to wrap your head around.”
Alumkal’s team discovered particular genes that were highly expressed in the baseline tumors that ultimately developed into double-negative prostate cancer, despite the fact that the baseline tumors had a similar appearance under the microscope. This finding implies that some tumors exist in a hybrid condition, initially fuel-dependent but susceptible to developing into double-negative prostate cancers after enzalutamide therapy.
Alumkal says, “results from the sequential sampling method suggest that enzalutamide is causing tumors to adapt, in some cases dramatically.”
Alumkal notes that “the gene signature he identified is preliminary, and the team has more work to do. Still, the fact that the DNA looks similar in the converters strongly indicates that enzalutamide is reprogramming tumors. We have more work to do, but it may be possible up-front to identify patients at greatest risk of having their tumor become fuel-independent after treatment with drugs like enzalutamide.”
- Westbrook, T.C., Guan, X., Rodansky, E. et al. Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity. Nat Commun 13, 5345 (2022). DOI: 10.1038/s41467-022-32701-6