期刊
CANCER LETTERS
卷 524, 期 -, 页码 206-218出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.10.022
关键词
CYH33; MYC; P300; BET; B cell lymphoma; PI3K
类别
This study revealed the importance of PI3Kα in B cell lymphoma cell proliferation, with the novel PI3Kα-selective inhibitor CYH33 showing superior activity against BCL compared to other inhibitors. Additionally, combination therapy of CYH33 with the BET inhibitor OTX015 was found to significantly enhance the treatment efficacy against BCL through inhibition of c-MYC expression and induction of cell cycle arrest and apoptosis, suggesting a promising therapeutic strategy.
Phosphatidylinositol 3-kinase (PI3K) 6-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3K alpha plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3K alpha was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3K alpha-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3K alpha-selective inhibitor Alpelisib and PI3K6-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated MYC-targets gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma.
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