Researchers Identify Key Mechanism Behind Castration-Resistant Prostate Cancer
A team of researchers from UC Davis, UC San Diego, and other institutions has identified a key mechanism behind aggressive prostate cancer. Published online today in Nature, the study shows that two long noncoding RNAs, PRNCR1 and PCGEM1, activate androgen receptors, circumventing androgen-deprivation therapy. In their active state, these receptors turn on genes that spur growth and metastasis, making these cancers highly treatment-resistant. The study illustrates how prostate cancer can thrive, even when deprived of hormones, and provides potential targets for new therapies.
High Expression of Long Noncoding RNAs in Aggressive Tumors
“Androgen-deprivation therapy will often put cancer in remission, but tumors come back, even without testosterone,” said contributor Christopher Evans, MD, Professor and Chair of the Department of Urology at the UC Davis School of Medicine. “We found that these long noncoding RNAs were activating the androgen receptor. When we knocked them out, cancer growth decreased in both cell lines and tumors in animals.”
Dr. Evans’ UC Davis group was part of a larger team, led by Michael Geoff Rosenfeld, MD, Professor at the Howard Hughes Medical Institute in the School of Medicine at UC San Diego, which has been eager to determine how androgen-dependent cancers become castration-resistant. These prostate cancers are very aggressive and usually fatal, but their continued growth, despite being deprived of hormones, is just now being better understood.
In this case, the aberrant starting mechanisms are long noncoding RNAs that regulate gene expression but do not code for proteins. Using patient samples, the group determined that both PRNCR1 and PCGEM1 are highly expressed in aggressive tumors. These RNAs bind to androgen receptors and activate them in the absence of testosterone, turning on as many as 617 genes.
Alternate Switching Mechanism at Work
Further investigation determined that one of these long noncoding RNAs is turning on androgen receptors by an alternate switching mechanism. This is critically important because many prostate cancer treatments work by blocking a part of the androgen receptor called the C-terminus. However, PCGEM1 activates another part of the receptor, called the N-terminus, which also turns on genes—with bad results.
“The androgen receptor is unique, if you knock out the C-terminus, that remaining part still has the ability to transcribe genes,” said Dr. Evans.
In addition, about 25% of these cancers have a mutated version of the androgen receptor that has no C-terminus. These receptors are locked in the “on” position, activating genes associated with tumor aggression.
Findings May Spur Development of New Therapies
Regardless of the receptor’s status, PRNCR1 and PCGEM1 are crucial to prostate cancer growth. In turn, knocking out these RNAs has a profound impact on gene expression, both in cell lines and animal models. The team used complementary genetic material, called antisense, to knock out the RNAs and observe how the tumors and cells responded. In each case, there was a direct relationship between RNA activity, gene expression, and cancer growth.
“These long noncoding RNAs are a required component for these castration-resistant cancers to keep growing,” said Dr. Evans. “Now we have preclinical proof of principle that if we knock them out, we decrease cancer growth.”
The research team’s next step is developing treatments that specifically target these long noncoding RNAs. That process has already begun.
“Most treatments for castration-resistant prostate cancer will get us around 2 to 3 years of survival,” said Dr. Evans. “We rarely cure these patients. The tumor will continue to evolve resistance mechanisms. But now that we have additional insight into what’s activating these receptors, we can begin developing new types of therapies to prevent it.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
