P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib

• Published in: Acta pharmacologica Sinica Vol. 43; no. 2; pp. 457 - 469
• Main Authors: Zhou, Xiao-ru, Li, Xiao, Liao, Li-ping, Han, Jie, Huang, Jing, Li, Jia-cheng, Tao, Hong-ru, Fan, Shi-jie, Chen, Zhi-feng, Li, Qi, Chen, Shi-jie, Ding, Hong, Yang, Ya-xi, Zhou, Bing, Jiang, Hua-liang, Chen, Kai-xian, Zhang, Yuan-yuan, Huang, Chuan-xin, Luo, Cheng
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.02.2022; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; Acetylation; Animals; Biomedical and Life Sciences; Biomedicine; Cell Cycle - drug effects; Cell Line, Tumor; Class Ia Phosphatidylinositol 3-Kinase - drug effects; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Drug resistance; Drug screening; Drug Synergism; Epigenetics; Female; Heterocyclic Compounds, 4 or More Rings - therapeutic use; Histones; Humans; Immunology; Internal Medicine; Lymphocytes; Lymphoma; Lymphoma, Mantle-Cell - drug therapy; Mantle cell lymphoma; MAP kinase; Medical Microbiology; Mice; Neoplasm Transplantation; p300-CBP Transcription Factors - antagonists & inhibitors; Pathogenesis; Pharmacology/Toxicology; Purines - therapeutic use; Quinazolinones - therapeutic use; Therapeutic targets; TOR protein; Transcription; Tumors; Vaccine; Xenografts; synergistic drug action; mantle cell lymphoma; P300/CBP; PI3Kδ; idelalisib; drug resistance; epigenetics
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00643-2

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.