STM2457 and enzalutamide suppress resistant prostate cancer

A study in Science Advances describes how enzalutamide-resistant prostate cancer sustains production of androgen receptor variant 7 (ARv7), a constitutively active transcription factor that drives disease progression. The authors identified ARv7 mRNA as a transcript carrying N6-methyladenosine (m6A) modifications. doi.org Enzalutamide treatment increased METTL3-dependent m6A methylation of ARv7 mRNA at the A1177 site. doi.org

The reader protein YTHDC2 recognizes this mark, which, according to the authors, enhances the translation efficiency of ARv7. doi.org Resistant tumors also showed elevated lactate metabolism. It regulated AR transcription through promoter-mediated epigenetic modifications at H3K9 and H3K14. doi.org Reactivated AR showed enhanced phase separation and up-regulated YTHDC2 expression at the transcriptional level, which closes the loop. doi.org

In vivo experiments showed that targeting the METTL3-YTHDC2-ARv7 axis suppressed progression of enzalutamide-resistant disease. The METTL3 inhibitor STM2457 combined with enzalutamide inhibited tumor growth, and the authors observed no toxicity. doi.org The results come from preclinical experiments.

The authors note that the ARv7 transcript is rare in castration-resistant prostate cancer, and this has limited recognition of its predictive value. They suggest that the clinical utility of ARv7 may need to be reconsidered in light of its m6A-dependent translational regulation. doi.org

METTL3 inhibitor STM2457 plus enzalutamide curbs resistant prostate cancer growth in vivo

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