CREBBP cooperates with the cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory diffuse large B-cell lymphoma

Sun, Yichen; Gao, Yan; Chen, Jianfeng; Huang, Ling; Deng, Peng; Chen, Jinghong; Chai, Kelila Xin Ye; Hong, Jing Han; Chan, Jason Yongsheng; He, Huixin; Wang, Yali; Cheah, Daryl Ming Zhe; Lim, Jing Quan; Chia, Burton Kuan Hui; Huang, Dachuan; Liu, Lizhen; Liu, Shini; Wang, Xiaoxiao; Teng, Yan; Pang, Diwen; Grigoropoulos, Nicholas F.; Teh, Bin Tean; Yu, Qiang; Lim, Soon Thye; Li, Wenyu; Ong, Choon Kiat; Huang, Huiqiang; Tan, Jian

doi:10.1016/j.canlet.2021.09.002

Cited by 16 publications

(14 citation statements)

References 41 publications

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“…Histone methyltransferases (HMTs) play crucial roles in epigenetic regulation by controlling histone lysine methylation, which may accelerate cancer progression [ 6 , 7 ]. A growing body of evidence indicates that dysregulated expression or mutation of various HMTs, such as lysine methyltransferase 2D (KMT2D), CREB-binding protein (CREBBP)and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), are some of the most common gene abnormalities in DLBCL, directly contributing to the molecular pathogenesis and progression of DLBCL [ 8 , 9 ]. For example, a gain-of-function mutation in EZH2 in DLBCL promotes germinal center proliferation [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription

Tian

Shi

et al. 2022

Cell Death Dis

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Genetic abnormalities in histone methyltransferases (HMTs) frequently occur in diffuse large B-cell lymphoma (DLBCL) and are related to its progression. SET and MYND domain containing 3 (SMYD3) is an HMT that is upregulated in various tumors and promotes their malignancy. However, to the best of our knowledge, the function of SMYD3 in DLBCL has not been investigated thus far. In the present study, 22 HMT genes related to cancer development were first selected according to current literature, and it was found that high SMYD3 expression was significantly associated with poor progression-free survival in patients with DLBCL. SMYD3 protein levels were upregulated and positively associated with poor prognosis and poor responsiveness to chemotherapy in patients with DLBCL. Functional examinations demonstrated that SMYD3 increased cell proliferation and the flux of aerobic glycolysis in DLBCL cells in vitro and in vivo and decreased cell sensitivity to doxorubicin in vitro. Moreover, SMYD3 could directly bind to specific sequences of Pyruvate Kinase M2 (PKM2) and promote DLBCL cell proliferation and aerobic glycolysis via H3K4me3-mediated PKM2 transcription. Clinically, SMYD3 expression positively correlated with that of PKM2, and high SMYD3 was significantly associated with high maximum standardized uptake value (SUVmax) detected by [(18)F]-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (PET/CT) in DLBCL samples. Concomitant expression of SMYD3 and PKM2 positively correlated with poor progression-free and overall survival in patients with DLBCL and may serve as novel biomarkers in DLBCL.

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Section: Introductionmentioning

confidence: 99%

SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription

Tian

Shi

et al. 2022

Cell Death Dis

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“…The CREBBP-deficient DLBCL cells were more sensitive to tucidinostat compared to CREBBPproficient DLBCL cells. In a phase II clinical trial of tucidinostat in DLBCL patients (Sun et al, 2021), DLBCL patients with CREBBP-deficiency exhibited a better response to tucidinostat treatment. Therefore, CREBBP was identified as a potential predictive biomarker for future patient stratification.…”

Section: Hematological Malignanciesmentioning

confidence: 99%

“…Mechanistic studies revealed that tucidinostat sensitivity was mediated through transcriptional inhibition of cell cycle progression. Identification of specific predictive biomarker and molecular mechanism allowed for precision tucidinostat treatment for specific R/R DLBCL patients (Sun et al, 2021).…”

Section: Hematological Malignanciesmentioning

confidence: 99%

“…Then AURKA inhibitors (Alisertib and VX680), identified through high-throughput drug screening, had shown synergistic effect with tucidinostat both in vivo and in vitro. Therefore, the combination of an AURKA inhibitor and tucidinostat is a novel therapeutic strategy for the treatment of R/R DLBCL (Sun et al, 2021).…”

Section: Hematological Malignanciesmentioning

confidence: 99%

“…Tucidinostat as a monotherapeutic agent for DLBCL is being evaluated in a phase II clinical trial in Japan and in combination with nivolumab as a first-line therapy for melanoma in a phase III clinical trial in the US. The clinical effect of tucidinostat has been shown in R/R DLBCL as a monotherapy, especially in those with CREBBP mutation (Sun et al, 2021). Tucidinostat exhibits an ORR of 39.06% (Shi et al, 2017) and the efficacy as a monotherapy in PTCL is evident.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment

Sun

Hong

Ning³

et al. 2022

Front. Pharmacol.

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Histone deacetylase (HDAC) is one of the most characterized epigenetic modifiers, modulating chromatin structure and gene expression, which plays an important role in cell cycle, differentiation and apoptosis. Dysregulation of HDAC promotes cancer progression, thus inhibitors targeting HDACs have evidently shown therapeutic efficacy in multiple cancers. Tucidinostat (formerly known as chidamide), a novel subtype-selective HDAC inhibitor, inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10. Tucidinostat is approved in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL), advanced breast cancer and R/R adult T-cell leukemia-lymphoma (ATLL). Compared with other HDAC inhibitors, tucidinostat shows notable antitumor activity, remarkable synergistic effect with immunotherapy, and manageable toxicity. Here, we comprehensively summarize recent advances in tucidinostat as both monotherapy and a regimen of combination therapy in both hematological and solid malignancies in clinic. Further studies will endeavor to identify more combination strategies with tucidinostat and to identify specific clinical biomarkers to predict the therapeutic effect.

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Chidamide plus R‐GDP for relapsed/refractory diffuse large B‐cell lymphoma in patients ineligible for autologous transplantation: A prospective, single‐arm, phase II study

Chen,

Xue,

Zhang

et al. 2024

Cancer Medicine

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BackgroundIn relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), a negative prognosis is frequently linked to heightened epigenetic heterogeneity. Chidamide, a selective histone deacetylase inhibitor, shows promise as a targeted therapy for R/R DLBCL by targeting abnormal epigenetic changes associated with poor prognosis.MethodsA cohort of 27 ineligible patients with R/R DLBCL participated in an open — label, single — arm study. Chidamide was administered orally at a dose of 30 mg twice weekly for one week during the induction monotherapy phase. The subsequent combination therapy phase involved oral chidamide at a dose of 20 mg twice weekly for two weeks, followed by a one‐week discontinuation period, in conjunction with intravenous R‐GDP every 21 days.ResultsAmong the cohort of 31 patients who underwent screening (median age: 67 years), 27 were ultimately included in the study, with 14 individuals successfully completing six cycles of C‐R‐GDP treatment. The overall best objective response rate was determined to be 79.1% (95% CI: 75.1%–83.3%), comprising a complete response rate of 45.8% (95% CI: 41.6%–49.9%) and a partial response rate of 33.3% (95% CI: 29.3%–37.4%). Within the subgroup of 14 patients who completed the full treatment regimen, the best objective response rate reached 100%, with 71.4% achieving complete response (n = 10) and 28.6% achieving partial response (n = 4). The median follow‐up period for these patients was 17.0 months, ranging from 3.5 to 55 months. Progression‐free survival was 5.9 months and overall survival was 48.3 months. Anemia was the most common adverse event, affecting all patients. Thrombocytopenia led to treatment interruption or dose reduction in 13 patients. Other common adverse events included hypocalcemia, hyponatremia, and hypokalemia. Three patients experienced grade 3 pneumonitis and one had grade 3 skin rash.ConclusionsChidamide combined with R‐GDP is a safe and effective treatment option for patients with R/R DLBCL who are not eligible for autologous stem cell transplantation.

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CREBBP cooperates with the cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory diffuse large B-cell lymphoma

Cited by 16 publications

References 41 publications

SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription

SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription

Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment

Chidamide plus R‐GDP for relapsed/refractory diffuse large B‐cell lymphoma in patients ineligible for autologous transplantation: A prospective, single‐arm, phase II study

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