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

Angela Su¹, Frank Ling¹, Camille Vaganay¹

¹INSERM UMR 944, IRSL, St Louis Hospital, University of Paris, Paris, France.

Cancer Discovery

|August 23, 2020

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 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.

Insights

Folate cycle disturbance, particularly MTHFR deficiency, can cause resistance to MYC-targeting therapies in acute myeloid leukemia (AML). Supplementing with CH3-THF may overcome this resistance and improve treatment outcomes.

Area of Science:

Cancer Biology
Metabolic Pathways
Epigenetics

Background:

MYC-targeting therapies show promise for cancer treatment, but predictors of sensitivity are limited.
Metabolic interventions may influence response to anticancer therapies.
The folate cycle plays a critical role in cellular metabolism and is linked to cancer progression.

Purpose of the Study:

To identify metabolic pathways impacting response to MYC-targeting therapies in acute myeloid leukemia (AML).
To investigate the role of the folate cycle and MTHFR enzyme activity in mediating resistance to BET and CDK7 inhibitors.
To explore the potential of metabolic interventions, such as CH3-THF supplementation, to overcome treatment resistance.

Main Methods:

Analysis of amino acid-related pathways connected to the folate cycle.
Assessment of folate restriction and MTHFR deficiency effects on MYC-targeting therapy response in AML cell lines, patient samples, and mouse models.
Investigation of mechanistic links involving histone methylation (H3K27/K9) and SPI1 transcriptional programs.

Main Results:

Folate cycle disturbance and MTHFR deficiency were found to induce resistance to MYC-targeting BET and CDK7 inhibitors in AML.
Reduced-function MTHFR polymorphisms, common in Caucasians, are associated with this resistance.
Supplementation with CH3-THF abrogated the resistance, suggesting a potential therapeutic strategy.

Conclusions:

Folate cycle status and MTHFR polymorphisms can predict sensitivity to MYC-targeting therapies in AML.
Folate cycle disturbance leads to epigenetic changes (reduced histone methylation) and transcriptional alterations that counteract BET inhibition.
CH3-THF supplementation is a low-risk intervention that can enhance the efficacy of BET inhibitors in AML.

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