TY - JOUR TI - P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib AU - Zhou, Xiao-ru AU - Li, Xiao AU - Liao, Li-ping AU - Han, Jie AU - Huang, Jing AU - Li, Jia-cheng AU - Tao, Hong-ru AU - Fan, Shi-jie AU - Chen, Zhi-feng AU - Li, Qi AU - Chen, Shi-jie AU - Ding, Hong AU - Yang, Ya-xi AU - Zhou, Bing AU - Jiang, Hua-liang AU - Chen, Kai-xian AU - Zhang, Yuan-yuan AU - Huang, Chuan-xin AU - Luo, Cheng T2 - Acta Pharmacologica Sinica AB - Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor. DA - 2021/04/13/ PY - 2021 DO - 10.1038/s41401-021-00643-2 DP - www.nature.com SP - 1 EP - 13 LA - en SN - 1745-7254 UR - https://www.nature.com/articles/s41401-021-00643-2 Y2 - 2021/04/13/16:17:25 ER -