Therapeutic Strategies to Inhibit MYC

McKeown, M.; Bradner, James E.

doi:10.1101/cshperspect.a014266

Cited by 199 publications

(218 citation statements)

References 138 publications

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“…BRD4 inhibition by JQ1, which competitively binds to the acetyl-lysine recognition motif, effectively induced regression of MYCdriven multiple myeloma and B-cell lymphomas (Filippakopoulos et al 2010;Nicodeme et al 2010;Delmore et al 2011). Other BRD4 inhibitors are also being evaluated as potential therapeutics for the treatment of MYC-driven cancers (see Bradner 2013).…”

Section: Therapeutic Strategies For Medulloblastomamentioning

confidence: 99%

Role of MYC in Medulloblastoma

Roussel

Robinson

2013

Cold Spring Harbor Perspectives in Medicine

134

109

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Since its discovery as an oncogene carried by the avian acute leukemia virus MC29 in myelocytomatosis (Roussel et al. 1979) and its cloning (Vennstrom et al. 1982), c-MYC (MYC), as well as its paralogs MYCN and MYCL1, has been shown to play essential roles in cycling progenitor cells born from proliferating zones during embryonic development, and in all proliferating cells after birth. MYC deletion induces cell-cycle exit or cell death, depending on the cell type and milieu, whereas MYC and MYCN amplification or overexpression promotes cell proliferation and occurs in many cancers. Here, we review the relationship of MYC family proteins to the four molecularly distinct medulloblastoma subgroups, discuss the possible roles MYC plays in each of these subgroups and in the developing cells of the posterior fossa, and speculate on possible therapeutic strategies targeting MYC.

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Section: Therapeutic Strategies For Medulloblastomamentioning

confidence: 99%

Role of MYC in Medulloblastoma

Roussel

Robinson

2013

Cold Spring Harbor Perspectives in Medicine

134

109

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“…Although there are many emerging efforts to target dysregulated MYC in cancer (reviewed in ref. 45), current approaches are focused on the development of strategies that exploit the reliance of these malignancies on MYC-governed processes. For example, in addition to our approach of targeting the ribosome, inhibitors of bromodomain and extraterminal (BET) proteins (e.g., JQ-1, iBET-151) that modulate RNA polymerase II-mediated transcription processes, including the expression of the c-MYC gene and downstream targets of MYC (46,47).…”

Section: Research Briefmentioning

confidence: 99%

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

et al. 2016

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Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYCdriven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE:Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1);[59][60][61][62][63][64][65][66][67][68][69][70]

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“…The role of Myc in tumor initiation and maintenance makes it an appealing target for cancer therapy (3), although targeting transcription factors has generally proven difficult. Despite an increasingly detailed mechanistic understanding of Myc structure and function, therapeutic strategies to directly manipulate Myc remain a historic challenge (4)(5)(6)(7), suggesting that alternative approaches are needed.…”

Section: Introductionmentioning

confidence: 99%