【摘 要】
：
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
【机 构】
：
Drug Discovery and Design Center,The Center for Chemical Biology,State Key Laboratory of Drug Resear
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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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