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BETs Need Greens: Folate Deficiency and Resistance to MYC-Targeted Therapies

Ludovica Marando1, Brian J P Huntly2

  • 1Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom. Department of Haematology, University of Cambridge, Cambridge, United Kingdom.

Cancer Discovery
|December 2, 2020
PubMed

Insights

A nongenetic resistance mechanism involving folate deficiency reactivates AML cell survival pathways under BET inhibition. This occurs via increased S-adenosylhomocysteine and reduced histone methylation, bypassing genetic alterations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Small-molecule inhibitors targeting transcriptional regulators like BET proteins and CDK7 show promise against various cancers.
  • Understanding resistance mechanisms is crucial for optimizing cancer therapies.

Purpose of the Study:

  • To identify nongenetic mechanisms of resistance to BET inhibitors in acute myeloid leukemia (AML).
  • To elucidate the molecular pathways involved in resistance to BET inhibition.

Main Methods:

  • Investigated the role of folate deficiency in mediating resistance to BET inhibitors.
  • Analyzed changes in S-adenosylhomocysteine levels and histone methylation patterns.
  • Examined the reactivation of specific transcriptional programs in AML cells.

Main Results:

  • Identified folate deficiency as a nongenetic mechanism conferring resistance to BET inhibitors.
  • Demonstrated that folate deficiency increases S-adenosylhomocysteine, leading to reduced repressive histone methylation.
  • Showed that this epigenetic alteration reactivates a transcriptional program promoting AML cell survival.

Conclusions:

  • Nongenetic factors, such as folate deficiency, can drive resistance to BET inhibitors in AML.
  • Targeting metabolic pathways or epigenetic modifications may overcome BET inhibitor resistance.
  • This finding offers new therapeutic strategies for AML patients resistant to BET inhibition.

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