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Cancer AND JQ1

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https://www.readbyqxmd.com/read/28143717/the-bet-bromodomain-inhibitor-jq1-radiosensitizes-non-small-cell-lung-cancer-cells-by-upregulating-p21
#1
Jian Wang, Ye Wang, Hong Mei, Zhongyuan Yin, Yuanyuan Geng, Tao Zhang, Gang Wu, Zhenyu Lin
Radiotherapy is an important treatment modality in the management of locally advanced non-small cell lung cancer (NSCLC). However, radioresistance markedly impairs its efficacy in clinic. Bromodomain and extra-terminal (BET) bromodomain inhibitors have demonstrated dramatic antitumor activity in several preclinical human cancer models. In this study, we investigated for the first time the effect of JQ1, a novel BET bromodomain inhibitor, on tumor cell radiosensitivity of NSCLC in vitro and in vivo. Our results demonstrated that JQ1 significantly enhanced the effect of irradiation in NSCLC cell lines through a c-myc-independent mechanism...
January 29, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28134933/inhibition-of-the-integrin-fak-signaling-axis-and-c-myc-synergistically-disrupts-ovarian-cancer-malignancy
#2
B Xu, J Lefringhouse, Z Liu, D West, L A Baldwin, C Ou, L Chen, D Napier, L Chaiswing, L D Brewer, D St Clair, O Thibault, J R van Nagell, B P Zhou, R Drapkin, J-A Huang, M L Lu, F R Ueland, X H Yang
Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor...
January 30, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28119527/runx3-is-oncogenic-in-natural-killer-t-cell-lymphoma-and-is-transcriptionally-regulated-by-myc
#3
V Selvarajan, M Osato, G S S Nah, J Yan, C Tae-Hoon, Dc-C Voon, Y Ito, M F Ham, M Salto-Tellez, N Shimizu, S-N Choo, S Fan, W-J Chng, S-B Ng
RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppresser in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal NK/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region...
January 25, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28118076/targeting-ampk-ulk1-mediated-autophagy-for-combating-bet-inhibitor-resistance-in-acute-myeloid-leukemia-stem-cells
#4
Ji Eun Jang, Ju-In Eom, Hoi-Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. We evaluated the levels of apoptosis and macroautophagy/autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+) CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations...
January 24, 2017: Autophagy
https://www.readbyqxmd.com/read/28100400/replication-study-bet-bromodomain-inhibition-as-a-therapeutic-strategy-to-target-c-myc
#5
Fraser Aird, Irawati Kandela, Christine Mantis
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al...
January 19, 2017: ELife
https://www.readbyqxmd.com/read/28074072/targeting-bet-proteins-improves-the-therapeutic-efficacy-of-bcl-2-inhibition-in-t-cell-acute-lymphoblastic-leukemia
#6
S Peirs, V Frismantas, F Matthijssens, W Van Loocke, T Pieters, N Vandamme, B Lintermans, M P Dobay, G Berx, B Poppe, S Goossens, B C Bornhauser, J-P Bourquin, P Van Vlierberghe
Inhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28061448/targeting-basal-like-breast-tumors-with-bromodomain-and-extraterminal-domain-bet-and-polo-like-kinase-inhibitors
#7
Cristina Nieto-Jiménez, Ana Alcaraz-Sanabria, Javier Pérez-Peña, Verónica Corrales-Sánchez, Gemma Serrano-Heras, Eva M Galán-Moya, Leticia Serrano-Oviedo, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Atanasio Pandiella, Alberto Ocaña
Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28059436/the-bet-bromodomain-inhibitor-jq1-suppresses-chondrosarcoma-cell-growth-via-regulation-of-yap-p21-c-myc-signaling
#8
Huan-Tian Zhang, Tao Gui, Yuan Sang, Jie Yang, Yu-Hang Li, Gui-Hong Liang, Thomas Li, Qing-Yu He, Zhen-Gang Zha
Chondrosarcoma, the second-most frequent primary bone malignancy, is generally more resistant to conventional chemotherapy and radiotherapy. Therefore, the development of an effective adjuvant therapy is necessary. Recently, targeting the epigenetic regulator such as bromodomain and extraterminal domain (BET) proteins has achieved great success. For instance, the bromodomain inhibitor JQ1 has been shown to inhibit the growth of several cancer cells both in vitro and in vivo. Herein we demonstrated that JQ1 significantly inhibited chondrosarcoma cell growth and colony formation...
January 6, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28026145/the-bromodomain-inhibitor-jq1-triggers-growth-arrest-and-apoptosis-in-testicular-germ-cell-tumours-in-vitro-and-in-vivo
#9
Sina Jostes, Daniel Nettersheim, Martin Fellermeyer, Simon Schneider, François Hafezi, Friedemann Honecker, Valerie Schumacher, Matthias Geyer, Glen Kristiansen, Hubert Schorle
Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20-40 years) and are classified as seminoma or non-seminoma. TGCTs are commonly treated by orchiectomy and chemo- or radiotherapy. However, a subset of metastatic non-seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small-molecule inhibitor JQ1 in tumour therapy, which interferes with the function of 'bromodomain and extraterminal (BET)' proteins...
December 27, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#10
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27872098/systematic-drug-screening-identifies-tractable-targeted-combination-therapies-in-triple-negative-breast-cancer
#11
Vikram B Wali, Casey G Langdon, Matthew A Held, James T Platt, Gauri A Patwardhan, Anton Safonov, Bilge Aktas, Lajos Pusztai, David F Stern, Christos Hatzis
Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments...
January 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/27864418/ampk-ulk1-mediated-autophagy-confers-resistance-to-bet-inhibitor-jq1-in-acute-myeloid-leukemia-stem-cells
#12
Ji Eun Jang, Ju In Eom, Hoi Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
PURPOSE: Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. EXPERIMENTAL DESIGN: We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+)CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations...
November 18, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27821592/bromodomain-and-extra-terminal-bet-protein-inhibitors-suppress-chondrocyte-differentiation-and-restrain-bone-growth
#13
Ningning Niu, Rui Shao, Guang Yan, Weiguo Zou
Small molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27803105/bet-inhibitors-suppress-aldh-activity-by-targeting-aldh1a1-super-enhancer-in-ovarian-cancer
#14
Yuhki Yokoyama, Hengrui Zhu, Jeong Heon Lee, Andrew V Kossenkov, Sherry Y Wu, Jayamanna M Wickramasinghe, Xiangfan Yin, Katherine C Palozola, Alessandro Gardini, Louise C Showe, Kenneth S Zaret, Qin Liu, David Speicher, Jose R Conejo-Garcia, James E Bradner, Zhiguo Zhang, Anil K Sood, Tamas Ordog, Benjamin G Bitler, Rugang Zhang
The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27769352/phospho-brd4-transcription-plasticity-and-drug-targeting
#15
REVIEW
Cheng-Ming Chiang
BRD4 is an epigenetic regulator and transcription cofactor whose phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. While the bromodomains of BET family proteins, including BRD4, BRD2, BRD3 and BRDT, have been the primary targets of small compounds such as JQ1, I-BET and MS417 that show promising anticancer effects against some hematopoietic cancer and solid tumors, drug resistance upon prolonged treatment necessitates a better understanding of alternative pathways underlying not only the resistance but also persistent BET protein dependence for identifying new targets and effective combination therapy strategies...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27764802/mycl-is-a-target-of-a-bet-bromodomain-inhibitor-jq1-on-growth-suppression-efficacy-in-small-cell-lung-cancer-cells
#16
Fuyumi Kato, Francesco Paolo Fiorentino, Andreu Alibés, Manuel Perucho, Montse Sánchez-Céspedes, Takashi Kohno, Jun Yokota
We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification...
October 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27717711/bet-bromodomain-is-a-novel-regulator-of-taz-and-its-activity
#17
Qiong Duan, Yi Xiao, Lingyan Zhu, Zhenzhen Liu, Xiaoxiao Mao, Zhengxiang Zhou, Chaonan Liao, Jinxing Cai, Fulian Huang, Zehao Liu, Jian Zeng, Ke Xia, Cheng Chang, Jun Qi, Zihua Chen, He Huang, Tianlun Yang
Transcriptional coactivator with PDZ-binding motif (TAZ) is a key transcriptional mediator of Hippo signaling that has been recently reported to mediate Wnt-activated transcription and serve as a component to suppress canonical Wnt/β-catenin activity. The Bromodomain and Extra-terminal domain (BET) family of proteins can recognize the acetylated lysine chain on histones and plays a critical role in transcriptional regulation. However, the mechanisms underlying transcriptional repression by the BET bromodomain are poorly understood...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27678457/the-mapk-pathway-regulates-intrinsic-resistance-to-bet-inhibitors-in-colorectal-cancer
#18
Yufang Ma, Lihong Wang, Leif R Neitzel, Sudan Loganathan, Nan Tang, Lili Qin, Crispi E Emily, Yan Guo, Stefan Knapp, Robert D Beauchamp, Ethan Lee, Jialiang Wang
PURPOSE: The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer (CRC)...
September 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27651315/brd4-regulates-breast-cancer-dissemination-through-jagged1-notch1-signaling
#19
Guillaume Andrieu, Anna H Tran, Katherine J Strissel, Gerald V Denis
The bromodomain and extraterminal (BET) proteins are epigenetic "readers" of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear how individual family members participate in cancer progression and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here, we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative breast cancer migration and invasion...
November 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27626654/bet-bromodomain-inhibition-promotes-anti-tumor-immunity-by-suppressing-pd-l1-expression
#20
Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R Rutkowski, Benjamin G Bitler, Michael J Allegrezza, Yuhki Yokoyama, Andrew V Kossenkov, James E Bradner, Jose R Conejo-Garcia, Rugang Zhang
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells...
September 13, 2016: Cell Reports
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