The folate cycle enzyme MTHFR is a critical regulator of cell response to MYC-targeting therapies

Angela Su, Frank Ling, Camille Vaganay, Gaetano Sodaro, Chaïma Benaksas, Reinaldo Dal Bello, Antoine Forget, Bryann Pardieu, Kevin H. Lin, Justine C. Rutter, Christopher F. Bassil, Gael Fortin, Justine Pasanisi, Iléana Antony-Debré, Gabriela Alexe, Jean François Benoist, Alain Pruvost, Yana Pikman, Jun Qi, Marie Hélène SchlageterJean Baptiste Micol, Giovanni Roti, Thomas Cluzeau, Hervé Dombret, Claude Preudhomme, Nina Fenouille, Lina Benajiba, Hava M. Golan, Kimberly Stegmaier, Camille Lobry, Kris C. Wood, Raphael Itzykson, Alexandre Puissant

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 MYCtargeting 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.

Original languageEnglish
Pages (from-to)1894-1911
Number of pages18
JournalCancer Discovery
Volume10
Issue number12
DOIs
StatePublished - 1 Dec 2020

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