2. Academic Validation
  3. P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib

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

  • Acta Pharmacol Sin. 2022 Feb;43(2):457-469. doi: 10.1038/s41401-021-00643-2.
Xiao-Ru Zhou  # 1 2 3,  Xiao Li 1 2,  Li-Ping Liao 1 2,  Jie Han 1,  Jing Huang 1 2,  Jia-Cheng Li 1 2,  Hong-Ru Tao 1 2,  Shi-Jie Fan 1 2,  Zhi-Feng Chen 1,  Qi Li 1,  Shi-Jie Chen 1,  Hong Ding 1,  Ya-Xi Yang 4,  Bing Zhou 4,  Hua-Liang Jiang 1,  Kai-Xian Chen 1 2 3,  Yuan-Yuan Zhang 5 6,  Chuan-Xin Huang 7,  Cheng Luo 8 9 10
Affiliations

Affiliations

  • 1 Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
  • 4 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Zhangyy@simm.ac.cn.
  • 6 University of Chinese Academy of Sciences, Beijing, 100049, China. Zhangyy@simm.ac.cn.
  • 7 Shanghai Institute of Immunology and Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. huangcx@shsmu.edu.cn.
  • 8 Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. cluo@simm.ac.cn.
  • 9 University of Chinese Academy of Sciences, Beijing, 100049, China. cluo@simm.ac.cn.
  • 10 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China. cluo@simm.ac.cn.
  • # Contributed equally.
PMID: 33850273 DOI: 10.1038/s41401-021-00643-2
Abstract

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.

Keywords

P300/CBP; PI3Kδ; drug resistance; epigenetics; idelalisib; mantle cell lymphoma; synergistic drug action.

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