"Most of the hypotheses have suggested that PTEN regulates the function of the androgen receptor pathway, which is opposite of what we show here," said Wu, who also is a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "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."
Wu's study showed that PTEN loss suppresses AR signaling and that leads cancer cells to become less dependent on the androgen receptor for survival. This is important, Wu said, because it addresses a key mechanism of resistance. Certain prostate cancers may resist hormone therapy and if you withdraw androgen as treatment, it enhances the activity of the PI3K pathway, which then takes over driving cancer growth. Both pathways must be hit to stifle growth of the cancer.
The study has important implications for those prostate patients with late stage disease, who often become resistant to hormone ablation therapy, said David J. Mulholland, a postdoctoral fellow in Wu's lab and first author of the study. Men who die of prostate cancer are those that become resistant to therapy and, as a consequence, their disease can spread or metastasize to other places, most often the bones.
"What we've shown here is a mechanism that could explain why anti-androgen therapy may fail in some patients," 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."
|Contact: Kim Irwin|
University of California - Los Angeles Health Sciences