JQ1, a BET‐bromodomain inhibitor, inhibits human cancer growth and suppresses PD‐L1 expression

Liu, Kaisheng; Zhou, Zhifan; Gao, Hengyuan; Yang, Fang; Qian, Yajun; Jin, Hongtao; Guo, Yuxi; Liu, Ying; Li, Haili; Zhang, Cheng; Guo, Jinan; Wan, Yong; Chen, Rui

doi:10.1002/cbin.11139

Cited by 27 publications

(26 citation statements)

References 28 publications

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“…Endogenous CDK4/6 plays an important role in regulating JQ1 sensitivity, and CDK4/6 inhibitors may exert synergetic effect with JQ1 (45). A study shows that BET inhibitor JQ1 can induce the differentiation and growth arrest in NC cell lines, and also exert anti-tumor effect in xenograft models of NC (70)(71)(72).…”

Section: Bet Inhibitorsmentioning

confidence: 99%

Advances in the pathogenesis and treatment of nut carcinoma: a narrative review

Wang¹,

Li²,

Tong³

et al. 2020

Transl Cancer Res TCR

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NUT carcinoma (NC) is a rare, highly invasive and fatal tumor and often misdiagnosed. It typically arises from the mediastinum and midline organs and has complicated pathogenesis and poor outcome. Genetically, its pathogenesis is related to a chromosomal rearrangement involving the NUTM1 gene. In most cases, the main oncoprotein is BRD4-NUT with a translocation between NUTM1 and BRD4 genes, but in a few cases, the oncoprotein is BRD3-NUT, or NSD3-NUT. Studies have shown that the histone hyperacetylation and BRD4 hyperphosphorylation may lead to the activation of cancer circuits.Abnormal production of microRNA, inactivation of tumor suppressor genes and abnormal activation of several signaling pathways are proposed as potential mechanisms underlying the pathogenesis of NC.Currently, there is no consensus on its standard treatment for NC. Extent of surgical resection with negative margins, initial radiotherapy and part of chemotherapy regimens may significantly associated with the improvement of progression-free survival (PFS) rate and overall survival (OS) rate. Some bromodomain and extraterminal inhibitors (BETis) have shown encouraging results in the clinical trials on NC, but delayed drug resistance is still an important issue that needs to be resolved. Histone deacetylase inhibitors are also found to possess the potential in the treatment of NC. Herein, we summarize recent advances in the pathogenesis and treatment of NC.

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Section: Bet Inhibitorsmentioning

confidence: 99%

Advances in the pathogenesis and treatment of nut carcinoma: a narrative review

Wang¹,

Li²,

Tong³

et al. 2020

Transl Cancer Res TCR

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“…The "adaptive immune resistance" represents a situation in which PD-L1 upregulation is driven by proinflammatory molecules produced by immune cells. IFN-γ and other soluble factors of the tumor microenvironment were able to upregulate PD-L1 in PC cells [10,13,94,103,106,112,119,126,128,139,152]. Conversely, when the "innate immune resistance" occurs, tumor cells autonomously upregulate PD-L1, under the influence of aberrant oncogenic pathways and without the induction of microenvironmental factors.…”

Section: Tumor Microenvironment and Mechanisms Of Tumor Immune-escape Mediated By The Pd-1/pd-l1 Axis: An Overviewmentioning

confidence: 99%

“…Table 1 summarizes the effects of PD-L1 extracellular regulators in PC cell lines and experimental studies. Treatment LASCPC, NCI-H660 ↑ // IFN-γ [126] Treatment DU145 = // IFN-γ [13,94,128] Treatment LNCaP = // IFN-γ [94] Treatment LAPC-4 = // IFN-γ [13] Treatment BPH1, C4-2, CWRR-1 = // IFN-γ [10,94,112,119,152] Treatment DU145 ↑ // IFN-γ [112] Treatment TRAMP-C2 Ras ↑ // IFN-γ [106] Treatment TRAMP-C1, MyC-CaP ↑ // Ab anti-IL-6 [134][135][136] Treatment C4-2, CWR22Rv1 ↓ // IL-6 [135] Treatment C4-2, CWR22Rv1 ↑ // IL-17 [145] Treatment LNCaP ↑ // TNF-α [145] Treatment LNCaP ↑ // Chemerin [105] Treatment of co-culture DU145 and T ↓ ↑ T cytotoxicity C5a [18] Treatment PC3, C4-2 ↑ // Hypoxia [65] Co-culture C4-2 and NK; CWR22Rv1 and NK ↑ ↓ NK cytotoxicity Act. Activation; ↑ Upregulation; ↓ Downregulation; = No alteration; // No effect was investigated.…”

Section: Experimental Studies: Overview Of Extracellular Factors Involved In Pd-l1 Regulation In Pcmentioning

confidence: 99%

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment

Palicelli

Croci

Bisagni

et al. 2021

IJMS

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The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

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“… 87 RCC cells treated with the bromine domain inhibitor JQ1 showed reduced proliferation and reduced PD‐L1/PD‐L2 expression, although the exact mechanism is unknown. 88 In addition, after neoadjuvant stereotactic radiotherapy (Neo‐SABR), the PD‐L1 expression in the tumor thrombus of patients with RCC and the tumor thrombus of the inferior vena cava increased, which may be attributed to the induction of immune‐related inflammatory cytokines. 89 …”

Section: Mechanisms Of Pd‐l1 Expression Alterations In Rccmentioning

confidence: 99%