
PRMT阻害剤の投与により、DNA修復関連遺伝子の発現が抑制され、PARP阻害剤に対する感受性が高まる。また、PRMT阻害剤はがん細胞の自然免疫応答を活性化させる。PRMT1阻害剤とPRMT5阻害剤の併用は、PARP阻害剤感受性をさらに高める。


coremsg

An “induced PARP inhibitor (PARPi) sensitivity by epigenetic modulation” strategy is being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARPi treatments. To expand its clinical applications and identify more efficient combinations, we performed a drug screen by combining PARPi with 74 well-characterized epigenetic modulators that target five major classes of epigenetic enzymes. Both type I PRMT inhibitor and PRMT5 inhibitor exhibit high combination and clinical priority scores in our screen. PRMT inhibition significantly enhances PARPi treatment-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMTs maintain the expression of genes associated with DNA damage repair and BRCAness and regulate intrinsic innate immune pathways in cancer cells. Analyzing large-scale genomic and functional profiles from TCGA and DepMap further confirms that PRMT1, PRMT4, and PRMT5 are potential therapeutic targets in oncology. Finally, PRMT1 and PRMT5 inhibition act synergistically to enhance PARPi sensitivity. Our studies provide a strong rationale for the clinical application of a combination of PRMT and PARP inhibitors in patients with HR-proficient ovarian or breast cancer.

### Competing Interest Statement

L.Z. and X.H. report having received research funding from AstraZeneca, Bristol-Myers Squibb/Celgene, and Prelude Therapeutics. Y.Z. is employees of GlaxoSmithKline. O.T. and H.M.C. are employees of AstraZeneca.

Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment

hr-proficient-卵巣がんおよび乳がん細胞におけるprmt活性の抑制がparp阻害剤治療に感受性を高める


HR-proficient 卵巣がんおよび乳がん細胞におけるPRMT活性の抑制がPARP阻害剤治療に感受性を高める
