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

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.

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Fig. 1: P300/CBP inhibitor A-485 was identified as a sensitizer to idelalisib by a combinatorial drug screen in MCL cells.
Fig. 2: Combination treatment with idelalisib and A-485 caused G1/S arrest and coinhibition of PI3K signaling in MCL cells.
Fig. 3: Antitumor efficiency of p300/CBP and PI3Kδ inhibition in vivo.
Fig. 4: Combination treatment with A-485 and idelalisib induces differential expression of numerous genes enriched in cancer-associated pathways, especially MAPK signaling, in MCL.
Fig. 5: The ERK-RSK-mTOR axis and upstream RTKs were inhibited by the combination treatment.
Fig. 6: Idelalisib treatment induces feedback activation of the MAPK pathway and upstream RTKs, which was blocked by A-485 via a decrease in histone acetylation at RTK promoters.

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Acknowledgements

The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (81625022, 91853205, 81821005 to CL, 81803554 to YZ, 81703415 to SC, 81973166 to BZ, 21820102008 to HJ); the Chinese Academy of Science grant (XDA12020353 to CL), KC Wong Education Foundation to BZ and CL, the National Science and Technology Major Project (2018ZX09711002-008-005 to BZ, 2018ZX09711002 to CL), Science and Technology Commission of Shanghai Municipality (18431907100 to HJ and 19XD1404700 to CL), the Youth Innovation Promotion Association (2017333 to YY).

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XRZ, XL, LPL, JH, JH, and ZFC conducted experiments. XRZ, YYZ analyzed data and wrote the paper. XL, JCL, HRT, SJF, QL, SJC, HD edited the paper. YXY, BZ provided reagents. HLJ, KXC, YYZ, CXH, and CL supervised the project and revised the papers. All authors have read and approved the paper.

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Correspondence to Yuan-yuan Zhang or Chuan-xin Huang or Cheng Luo.

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Zhou, Xr., Li, X., Liao, Lp. et al. P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00643-2

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Keywords

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

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