A team of Cleveland Clinic-led researchers have discovered how prostate cancer tumor cells evade therapy, and in the process have, have identified a promising new treatment strategy that can circumvent the drug resistance that often develops.

Antiandrogen strategies are the backbone of prostate cancer treatments, but they are prone to the development of tumor resistance. The research showed that androgen blockade in prostate cancer leads to derepression of retroelements followed by a double-stranded RNA (dsRNA)-stimulated interferon response that blocks tumor growth.

The findings, published this week in Proceedings of the National Academy of Sciences (PNAS), show that as prostate cancer drug resistance develops, a complex tumor response occurs during which tumors briefly express “virus-like” repeat elements and trigger an immune stimulatory response.

“This study reveals that antiandrogen therapy induces viral mimicry responses that are crucial for antitumor activity,” the researchers wrote. “H3K9 trimethylation to silence endogenous repeat elements is essential for regaining heterochromatin stability and progression to antiandrogen resistance in prostate cancer. We found that the H3K9 trimethylation machinery is linked to poor outcomes in men with prostate cancer.”

The team’s forward genetic approach identified H3K9 trimethylation (H3K9me3) as an essential epigenetic adaptation to antiandrogens. The researchers noted that this “enabled transcriptional silencing of retroelements that otherwise stimulate interferon signaling and glucocorticoid receptor expression. Elevated expression of terminal H3K9me3 writers was associated with poor patient hormonal therapy outcomes. Forced expression of H3K9me3 writers conferred resistance, whereas inhibiting H3K9-trimethylation writers and readers restored retroelement expression, blocking antiandrogen resistance. Our work reveals a drug resistance axis that integrates multiple cellular signaling elements and identifies potential pharmacologic vulnerabilities.

“Blockade of this [H3K9 trimethylation] epigenetic axis can resensitize drug-resistant tumors and elicit cytotoxic interferon responses. Antiandrogen timing and regulation of the H3K9 methylation—endogenous repeat elements—interferon axis should be considered in the development of novel epigenetic therapies and immunotherapeutic strategies for prostate cancer.”

Nima Sharifi, M.D., director of the Genitourinary Malignancies Research Center at Cleveland Clinic’s Lerner Research Institute and the Kendrick Family Endowed Chair for Prostate Cancer Research, who was lead author of the study said: “This is significant as it may tell us how prostate cancers, which are known not to respond to immunotherapies, could then flip on responsiveness to these therapies. More research is needed but this could be a promising strategy for overcoming this drug resistance and immune evasion in prostate cancer.”

Sharifi, was joined in the research by co-first authors Drs. Mehdi Baratchian and Ritika Tiwari. Collaborating institutions include Royal Marsden Hospital in the U.K. and Princess Margaret Cancer Center in Toronto.

Also of Interest