BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells

Muralidharan, Somsundar Veppil; Bhadury, Joydeep; Nilsson, Lisa M.; Green, L C; McLure, Kevin G.; Nilsson, Jonas A.

doi:10.1038/onc.2015.521

Cited by 53 publications

(49 citation statements)

References 56 publications

(69 reference statements)

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“…197 In this situation, combination of BET inhibitors and corresponding signaling negative modulator may overcome the BET inhibition resistance. 198 In addition, the aforementioned one drug with polypharmacology holds great promise for mitigating resistance in cancer therapy and may guide the next generation of efficacious BRD4 inhibitors as anticancer agents.…”

Section: Concluding Remarks: Challenges and Opportunitiesmentioning

confidence: 99%

Drug Discovery Targeting Bromodomain-Containing Protein 4

et al. 2017

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BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein–protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.

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Section: Concluding Remarks: Challenges and Opportunitiesmentioning

confidence: 99%

Drug Discovery Targeting Bromodomain-Containing Protein 4

et al. 2017

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“…JQ1 was found to inhibit the bromodomain BRD4, reducing MYC transcription 130–132. Decreased expression of c-MYC and restoration of apoptosis can also be obtained by dual mTOR inhibitors,133 and BET inhibitors can synergize with inhibitors of the upstream replication stress sensor ATR, blocking progression of c-MYC + lymphoma cells 134. THZ1 was developed as a novel highly selective covalent inhibitor of CDK7 , which, by linking to a cysteine residue, specifically downregulates MYC expression 130.…”

Section: New Drugs and Treatment Modalitiesmentioning

confidence: 99%

Burkitt lymphoma in adolescents and young adults: management challenges

Dozzo¹,

Carobolante²,

Donisi³

et al. 2016

AHMT

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About one-half of all Burkitt lymphoma (BL) patients are younger than 40 years, and one-third belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25–40 years, based on selection criteria used in different reports. BL is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes. It presents as sporadic, endemic, or epidemic disease. Endemicity is pathogenetically linked to an imbalance of the immune system which occurs in African children infected by malaria parasites and Epstein–Barr virus, while the epidemic form strictly follows the pattern of infection by HIV. BL shows propensity to extranodal involvement of abdominal organs, bone marrow, and central nervous system, and can cause severe metabolic and renal impairment. Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multiagent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody rituximab. When carefully applied with appropriate supportive measures, these modern programs achieve a cure rate of approximately 90% in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to date. The challenges ahead concern the following: optimization of management in underdeveloped countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography and minimal residual disease assays; and the assessment in these and the few refractory/relapsed ones of new monoclonals (ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B-cell malignancies.

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“…Yet other studies exploited the concept of synthetic lethality toward identification of effective therapeutic targets in tumors addicted to deregulated MYC expression/activity, based on either reverse‐genetic screens or select targeting (eg, ), or pharmacologic intervention with inhibitory compounds against various cellular proteins, including kinases, BET Bromodomains (eg, ), Histone deacetylases (HDACs), PARP, glycolytic enzymes, and others …”

Section: Targeting Myc Addictionmentioning

confidence: 99%

MYC in Germinal Center‐derived lymphomas: Mechanisms and therapeutic opportunities

Bisso

Sabò

Amati

2019

Immunological Reviews

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Summary The rearrangement of immunoglobulin loci during the germinal center reaction is associated with an increased risk of chromosomal translocations that activate oncogenes such as MYC, BCL2 or BCL6, thus contributing to the development of B‐cell lymphomas. MYC and BCL2 activation are initiating events in Burkitt's (BL) and Follicular Lymphoma (FL), respectively, but can occur at later stages in other subtypes such as Diffuse Large‐B Cell Lymphoma (DLBCL). MYC can also be activated during the progression of FL to the transformed stage. Thus, either DLBCL or FL can give rise to aggressive double‐hit lymphomas (DHL) with concurrent activation of MYC and BCL2. Research over the last three decades has improved our understanding of the functions of these oncogenes and the basis for their cooperative action in lymphomagenesis. MYC, in particular, is a transcription factor that contributes to cell activation, growth and proliferation, while concomitantly sensitizing cells to apoptosis, the latter being blocked by BCL2. Here, we review our current knowledge about the role of MYC in germinal center B‐cells and lymphomas, discuss MYC‐induced dependencies that can sensitize cancer cells to select pharmacological inhibitors, and illustrate their therapeutic potential in aggressive lymphomas—and in particular in DHL, in combination with BCL2 inhibitors.

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BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells

Cited by 53 publications

References 56 publications

Drug Discovery Targeting Bromodomain-Containing Protein 4

Drug Discovery Targeting Bromodomain-Containing Protein 4

Burkitt lymphoma in adolescents and young adults: management challenges

MYC in Germinal Center‐derived lymphomas: Mechanisms and therapeutic opportunities

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