Targeting Cancer Cells with BET Bromodomain Inhibitors

Xu, Yali; Vakoc, Christopher R.

doi:10.1101/cshperspect.a026674

Cited by 163 publications

(136 citation statements)

References 111 publications

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“…A comparison of responses to JQ1 and IBET151 revealed a high correlation (R=0.91), suggesting that both compounds have similar efficacies and on-target activity in vitro ( Figure 1D). Consistent with previous studies, a correlative genomic analysis of response to BET inhibition did not detect a significant enrichment for any recurrent/driver breast cancer genomic aberration within resistant or sensitive cell lines ( Figure S1A) (8,(21)(22). The lack of genomic markers predictive of response to BETi in breast cancer necessitates deeper mechanistic analyses to discover biomarkers likely to identify patients who will benefit from BETi.…”

Section: Breast Cancer Cells Have Differential Responses To Bet Inhibsupporting

confidence: 85%

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Yan

Wang

Luna

et al. 2019

Preprint

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The development of effective targeted therapies for the treatment of basal-like breast cancers remains challenging. Here, we demonstrate that BET inhibition induces a multi-faceted adaptive response program leading to MCL1 protein-driven evasion of apoptosis in breast cancers. Consequently, co-targeting MCL1 and BET is highly synergistic in in vitro and in vivo breast cancer models. Drug response and genomics analyses revealed that MCL1 copy number alterations, including low-level gains, are selectively enriched in basal-like breast cancers and associated with effective BET and MCL1 co-targeting. The mechanism of adaptive response to BET inhibition involves upregulation of critical lipid metabolism enzymes including the rate-limiting enzyme stearoyl-CoA desaturase (SCD). Changes in the lipid metabolism are associated with increases in cell motility and membrane fluidity as well as transitions in cell morphology and adhesion. The structural changes in the cell membrane leads to re-localization and activation of HER2/EGFR which can be interdicted by inhibiting SCD activity. Active HER2/EGFR, in turn, induces accumulation of MCL1 protein and therapeutic vulnerability to MCL1 inhibitors. The BET protein, lipid metabolism and receptor tyrosine kinase activation cascade is observed in patient cohorts of basal-like and HER2-amplified breast cancers. The high frequency of MCL1 chromosomal amplifications (>30%) and gains (>50%) in basal-like breast cancers suggests that BET and MCL1 co-inhibition may have therapeutic utility in this aggressive subtype.

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Section: Breast Cancer Cells Have Differential Responses To Bet Inhibsupporting

confidence: 85%

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Yan

Wang

Luna

et al. 2019

Preprint

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“…The bromodomain and extra‐terminal domain (BET) motif‐containing family of proteins binds acetylated lysines on histone tails and recruits histone‐modifying enzymes to regulate chromatin structure and gene expression. The bromodomain family consists of four proteins (BRD2, BRD3, BRD4, and BRDT), and compelling preclinical data demonstrate that BET domain targeting may be a valuable strategy for treating a wide range of solid tumors and hematologic malignancies . The BET inhibitor JQ1 exhibited potent antiproliferative effects associated with cell cycle arrest and cellular senescence of MM cell lines and primary CD138+ patient‐derived MM cells and significantly decreased MM tumor burden in vivo .…”

Section: Epigenetic Targeting As Treatment Of Mmbdmentioning

confidence: 99%

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

2019

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Multiple myeloma (MM) bone disease is characterized by the development of osteolytic lesions, which cause severe complications affecting the morbidity, mortality, and treatment of myeloma patients. Myeloma tumors seeded within the bone microenvironment promote hyperactivation of osteoclasts and suppression of osteoblast differentiation. Because of this prolonged suppression of bone marrow stromal cells’ (BMSCs) differentiation into functioning osteoblasts, bone lesions in patients persist even in the absence of active disease. Current antiresorptive therapy provides insufficient bone anabolic effects to reliably repair MM lesions. It has become widely accepted that myeloma‐exposed BMSCs have an altered phenotype with pro‐inflammatory, immune‐modulatory, anti‐osteogenic, and pro‐adipogenic properties. In this review, we focus on the role of epigenetic‐based modalities in the establishment and maintenance of myeloma‐induced suppression of osteogenic commitment of BMSCs. We will focus on recent studies demonstrating the involvement of chromatin‐modifying enzymes in transcriptional repression of osteogenic genes in MM‐BMSCs. We will further address the epigenetic plasticity in the differentiation commitment of osteoprogenitor cells and assess the involvement of chromatin modifiers in MSC‐lineage switching from osteogenic to adipogenic in the context of the inflammatory myeloma microenvironment. Lastly, we will discuss the potential of employing small molecule epigenetic inhibitors currently used in the MM research as therapeutics and bone anabolic agents in the prevention or repair of osteolytic lesions in MM. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…They are the only domains, which bind specifically to histone acetylation marks (Jain & Barton, 2017). Recently, the anti-cancer efficacy of inhibitors against the bromodomain and extra-terminal domain-containing (BET) protein family have been evaluated in several cancers, such as prostate, breast, colon, intestine, pancreas, liver, lung, brain, oral squamous cell carcinoma, and leukemias (Sahai et al, 2016;Saenz et al, 2017;Xu & Vakoc, 2017;Sahni & Keri, 2018;Zhang et al, 2018;Baldan et al, 2019). Even though combined treatment with HDAC and BET inhibitors (BETi) revealed additive or synergistic effects in several cancer entities, such as cutaneous T-cell lymphoma, neuroblastoma, glioblastoma, non-small cell lung cancer, adenocarcinoma, and colon cancer (Mazur et al, 2015;Shahbazi et al, 2016;Adeegbe et al, 2017;Meng et al, 2018;Rajendran et al, 2019;Zhao et al, 2019), so far only few studies described the mono-and combined treatment options with BETis in GCTs.…”

Section: Hdac Inhibitors Plus Bromodomain Protein Inhibitorsmentioning

confidence: 99%

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

Oing

Skowron²,

Bokemeyer

et al. 2019

Andrology

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Background: Type II germ cell tumors represent the most common solid malignancy in men aged 15-45 years. Despite high cure rates of >90% over all stages, 10-15% of advanced patients develop treatment resistance and potentially succumb to their disease. Treatment of refractory germ cell tumors remains unsatisfactory, and new approaches are needed to further improve outcomes. Objectives: With this narrative review, we highlight epigenetic mechanisms related to resistance to standard systemic treatment, which may act as promising targets for novel combined epigenetic treatment approaches. Materials and methods: A comprehensive literature search of PubMed and MEDLINE was conducted to identify original and review articles on resistance mechanisms and/or epigenetic treatment of germ cell tumors in vitro and in vivo. Review articles were hand-searched to identify additional articles. Results: Distinct epigenetic phenomena have been linked to chemotherapy resistance in germ cell tumors, among which DNA hypermethylation, histone acetylation, and bromodomain proteins appear as promising targets for therapeutic exploitation. Inhibitors of key regulators, for example DNA methyltransferases (e.g. decitabine, guadecitabine), histone deacetylases (e.g. romidepsin), and bromodomain proteins (e.g. JQ1) decreased cell viability, triggered apoptosis, and growth arrest. Additionally, these epigenetic drugs induced differentiation and led to loss of pluripotency and re-sensitization towards cisplatin in cell lines and animal models. Discussion: Epigenetic treatments hold promise to (i) reduce the treatment burden of and (ii) overcome resistance to standard cisplatin-based chemotherapy. Combined approaches may enhance activity, while the ideal target and treatment combination of epigenetic drugs, either with another epigenetic agent or conventional cytotoxic agents need to be defined. Conclusion: Epigenetic (combination) treatment for germ cell tumors should be further explored in pre-clinical and clinical research for its potential to further improve germ cell tumor treatment.

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Targeting Cancer Cells with BET Bromodomain Inhibitors

Cited by 163 publications

References 111 publications

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

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