Histone deacetylase inhibitor induces acetyl-CoA depletion leading to lethal metabolic stress in RAS-pathway activated cells

Basseville, A.; Violet, P.-C.; Safari, M.; Sourbier, C.; Linehan, M.; Robey, R. W.; Levine, M.; Sackett, D. L.; Bates, S. E.

doi:10.1101/2022.01.31.478570

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bioRxiv · 10.1101/2022.01.31.478570

Histone deacetylase inhibitor induces acetyl-CoA depletion leading to lethal metabolic stress in RAS-pathway activated cells

Basseville, A.·Violet, P.-C.·Safari, M.·Sourbier, C.·Linehan, M.·Robey, R. W.·Levine, M.·Sackett, D. L.·Bates, S. E.

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Abstract

RAS-mutant cancers are among the most refractory to treatment. Apart from new G12C genotype targeted therapies, strategies to kill RAS-mutant cells by directly targeting RAS or its downstream effectors have been mostly unsuccessful, mainly due to pathway redundancy and heterogeneities in RAS-induced phenotypes. Here we identified a RAS-phenotype that can be targeted by the histone deacetylase inhibitor (HDACi) romidepsin. We showed that the hyperacetylation induced by romidepsin depleted acetyl-CoA, the cell donor substrate for acetylation, and led to metabolic stress and death in KRAS-activated cells. Elastic net analysis on transcriptomics from a 608-cell panel confirmed that HDACi sensitivity was linked to a difference in profiles in two pathways involved in acetyl-CoA metabolism. The analysis of a clinical dataset confirmed that perturbation of the two acetyl-CoA pathways were correlated with HDACi sensitivity in patients treated with belinostat. Our analysis suggests the potential utility of a RAS-associated acetyl-CoA phenotype to sharpen treatment choices for RAS-activated tumors.

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Basseville, A., Violet, P.-C., Safari, M., Sourbier, C., Linehan, M., Robey, R. W., Levine, M., Sackett, D. L., Bates, S. E.. 2022-02-01. Histone deacetylase inhibitor induces acetyl-CoA depletion leading to lethal metabolic stress in RAS-pathway activated cells. https://doi.org/10.1101/2022.01.31.478570

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