Skip to main content

The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.

Publication ,  Journal Article
Su, A; Ling, F; Vaganay, C; Sodaro, G; Benaksas, C; Dal Bello, R; Forget, A; Pardieu, B; Lin, KH; Rutter, JC; Bassil, CF; Fortin, G; Alexe, G ...
Published in: Cancer Discov
December 2020

Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies. SIGNIFICANCE: Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.See related commentary by Marando and Huntly, p. 1791.This article is highlighted in the In This Issue feature, p. 1775.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

December 2020

Volume

10

Issue

12

Start / End Page

1894 / 1911

Location

United States

Related Subject Headings

  • U937 Cells
  • Proto-Oncogene Proteins c-myc
  • Neoplasms
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Su, A., Ling, F., Vaganay, C., Sodaro, G., Benaksas, C., Dal Bello, R., … Puissant, A. (2020). The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies. Cancer Discov, 10(12), 1894–1911. https://doi.org/10.1158/2159-8290.CD-19-0970
Su, Angela, Frank Ling, Camille Vaganay, Gaetano Sodaro, Chaïma Benaksas, Reinaldo Dal Bello, Antoine Forget, et al. “The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.Cancer Discov 10, no. 12 (December 2020): 1894–1911. https://doi.org/10.1158/2159-8290.CD-19-0970.
Su A, Ling F, Vaganay C, Sodaro G, Benaksas C, Dal Bello R, et al. The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies. Cancer Discov. 2020 Dec;10(12):1894–911.
Su, Angela, et al. “The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.Cancer Discov, vol. 10, no. 12, Dec. 2020, pp. 1894–911. Pubmed, doi:10.1158/2159-8290.CD-19-0970.
Su A, Ling F, Vaganay C, Sodaro G, Benaksas C, Dal Bello R, Forget A, Pardieu B, Lin KH, Rutter JC, Bassil CF, Fortin G, Pasanisi J, Antony-Debré I, Alexe G, Benoist J-F, Pruvost A, Pikman Y, Qi J, Schlageter M-H, Micol J-B, Roti G, Cluzeau T, Dombret H, Preudhomme C, Fenouille N, Benajiba L, Golan HM, Stegmaier K, Lobry C, Wood KC, Itzykson R, Puissant A. The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies. Cancer Discov. 2020 Dec;10(12):1894–1911.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

December 2020

Volume

10

Issue

12

Start / End Page

1894 / 1911

Location

United States

Related Subject Headings

  • U937 Cells
  • Proto-Oncogene Proteins c-myc
  • Neoplasms
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Male