Prostate Cancer Drug Resistance Mediated by Epigenetic Changes

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Epigenetic changes in the tumor microenvironment may explain why prostate cancer patients develop resistance to androgen signaling deprivation therapy.
Epigenetic changes in the tumor microenvironment may explain why prostate cancer patients develop resistance to androgen signaling deprivation therapy.

Epigenetic changes in the nearby tumor microenvironment may mediate the transformation of prostate cancer to a more aggressive neuroendocrine subtype as well as confer the development of resistance to androgen signaling deprivation therapy (ADT), according to a study.The study findings were published online September 4, 2018, in The Journal of Clinical Investigation.

Researchers identified RAS protein activator–like 3 (RASAL3) as epigenetically silenced in human prostatic cancer-associated fibroblasts (CAF). The silencing of RASAL3, a Ras inhibitor, was shown to activate the Ras pathway and promote macropinocytosis-mediated glutamine synthesis. Exposure to ADT was found to further promote RASAL3 epigenetic silencing and glutamine secretion.

Inhibition of macropinocytosis and glutamine transport led to tumor shrinkage in mice, suggesting glutamine uptake by the tumor was necessary for growth. Further, blocking the uptake of glutamine reversed ADT resistance in mice.

“This is the first demonstration, to our knowledge, of epigenetic Ras regulation in CAF consequently contributing to cancer progression,” the study authors wrote.

The study authors further validated their findings by measuring blood glutamine levels in a small group of 28 prostate cancer patients, of whom 10 developed therapeutic resistance and 18 did not. Glutamine levels in human blood samples were found to be higher in prostate cancer patients on ADT who developed resistance than patients with therapeutically responsive disease (odds ratio = 7.451, P= .02).

“Our data suggested that plasma glutamine can be used as a prognostic marker following ADT response and development of resistance,” the study authors concluded. 

Reference

  1. Mishra R, Haldar S, Placencio V, et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming [published online September 4, 2018]. J Clin Invest. doi: 10.1172/JCI99397

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