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Targeting MYC dependence in cancer by inhibiting BET bromodomains

Jennifer A Mertz1, Andrew R Conery, Barbara M Bryant

  • 1Constellation Pharmaceuticals, Inc, Cambridge, MA 02142, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 28, 2011
PubMed

Insights

Small molecule inhibitors targeting BET proteins effectively suppress MYC transcription, leading to cancer cell death. This approach shows promise for treating MYC-driven cancers like leukemia and lymphoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The MYC transcription factor is crucial for cell function but often dysregulated in cancers.
  • Targeting MYC is challenging due to complex regulatory mechanisms and protein-DNA interactions.

Purpose of the Study:

  • To investigate the efficacy of BET inhibitors in suppressing MYC transcription and its downstream effects.
  • To evaluate the therapeutic potential of BET inhibitors in MYC-driven malignancies.

Main Methods:

  • Utilized small molecule inhibitors targeting BET family chromatin adaptors.
  • Assessed MYC gene transcription, protein levels, and cell cycle progression (G1 arrest, apoptosis).
  • Employed xenograft models of Burkitt's lymphoma and acute myeloid leukemia.

Main Results:

  • BET inhibitors rapidly and potently abrogated MYC gene transcription across various gene loci.
  • Inhibition led to reduced MYC levels, G1 arrest, and apoptosis in leukemia and lymphoma cells.
  • Reactivation of the p21 tumor suppressor was observed, and BET inhibitors showed significant antitumor activity in vivo.

Conclusions:

  • Pharmacologic inhibition of MYC is achievable by targeting BET bromodomains.
  • BET inhibitors demonstrate clinical potential for treating cancers driven by aberrant MYC expression.

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