Epigenetic Triggers of Treatment-Resistant Neuroendocrine Prostate Cancer

Study provides insight into how prostate cancer transitions to an aggressive, treatment-resistant subtype following anti-androgen therapy.

Researchers have come closer to identifying how prostate cancer becomes treatment resistant, which could lead to the development of targeted therapies to prevent resistance before it begins, according to a new study published in Cancer Cell.

For prostate cancer, anti-androgen therapies can be an effective treatment. However, patients who receive these treatments are more likely to develop neuroendocrine prostate cancer (NEPC), a treatment-resistant subtype of the disease for which there is no current effective therapy.

In the development of NEPC, the tumor cells are completely reprogrammed, making it difficult to treat. The study aimed to identify the molecular triggers that may initiate the transformation from prostate cancer to NEPC.

“Similar to bacteria that gain resistance to antibiotics, tumors can become resistant to anti-cancer drugs by ‘remodeling’ their environment and developing strategies to evade targeted therapies,” senior author Maria Diaz-Meco, PhD, professor in the Cancer Metabolism and Signaling Networks at Sanford Burnham Prebys, said in a press release. “As targeted therapies become more potent, putting more stress on tumors, we expect to see drug resistance become more common.”

For the study, the researchers examined tissue samples from men with metastatic NEPC, prostate cancer cell lines, and a new mouse model of NEPC. They found that the NEPC cells upregulate the synthesis of a metabolite called serine, a non-essential amino acid that could be blocked with minimal or no effect on normal cells. Additionally, the cancer cells were found to use a communication pathway called mTORC1/ATF4 to accelerate the synthesis of serine, which allows the tumor to grow faster and epigenetically switch to the NEPC mode.

“Our study shows that in a form of treatment-resistant prostate cancer, a tumor suppressor gene called protein kinase C lambda/iota is downregulated,” Dr Diaz-Meco wrote. “We subsequently identified metabolic and epigenetic vulnerabilities which are possible routes to prevent treatment resistance from arising.”

Additionally, the researchers identified the involvement of a protein that regulates the positions of lysosomes in the tumor’s transformation. Epigenetic patterns associated with NEPC were also discovered, including an expression of an enzyme called phosphoglycerate dehydrogenase (PHGDH), according to the study. The findings revealed a currently FDA-approved treatment called decitabine that may hold promise as an NEPC treatment, called decitabine, which inhibits epigenetic changes.

“Luckily, prostate cancer is a cancer type that is well characterized, which helps us better understand the mechanisms behind treatment resistance,” Dr Diaz-Meco concluded.

The researchers plan to expand on their findings to identify drug therapies that can block PHGDG in hopes of uncovering more promising implications for the future treatment of NEPC.

References

How prostate cancer becomes treatment resistant [news release]. Sanford Burnham Prebys Medical Discovery Institute. https://sbpdiscovery.org/press/how-prostate-cancer-becomes-treatment-resistant. Published February 28, 2019. Accessed March 4, 2019.

Diaz-Meco MT, Reina-Campos M, Linares JF, et al. Increased serine and one-carbon pathway metabolism by PKCλ/ι deficiency promotes neuroendocrine prostate cancer. Cancer Cell. February 28, 2019. Doi: https://doi.org/10.1016/j.ccell.2019.01.018