Some prostate cancers resist ADT by activating alternate pathway for growth

A type of prostate cancer is able to resist conventional hormone ablation therapy by activating a survival cell-signaling pathway, say researchers from UCLA’s Jonsson Comprehensive Cancer Center, Los Angeles.

The authors, led by Hong Wu, MD, PhD, say that PTEN-negative prostate cancers could be more effectively treated using a combination of drugs that target the androgen receptor cell signaling pathway and the compensating survival pathway, called the PI3K/AKT/mTOR pathway.

"The most significant take-home message from this study is that certain prostate cancers can resist androgen deprivation therapy by activating an alternate pathway to drive its growth," Dr. Wu said. “We found that these two pathways are talking to each other, almost like regulatory circuitry, and helping each other get around attempts to kill the cancer. When we suppress one of these pathways, it essentially feeds the other.

"Most of the hypotheses have suggested that PTEN regulates the function of the androgen receptor pathway, which is opposite of what we show here. We had thought that when PTEN was lost, it activated the androgen receptor pathway, driving cancer growth. What we’ve found suggests that if PTEN is lost in cancer cells, then the cancer cells become androgen receptor-independent and rely on the PI3K pathway for growth and survival."

The study has important implications for those prostate patients with late-stage disease, who often become resistant to hormone-ablation therapy, said first author David J. Mulholland, MS, PhD.

"What we’ve shown here is a mechanism that could explain why anti-androgen therapy may fail in some patients," Dr. Mulholland said. "Their cancer cells adapted to the low androgen receptor function and compensated by activating a survival pathway. It was a surprising result to show that these cells could continue to live without the androgen receptor signaling. Combining drugs that hit both pathways will be much more effective than using one drug alone."

Results from the study were published in Cancer Cell (2011; 19:792-804).