SCD inhibition eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy

Identification of specific and therapeutically actionable vulnerabilities in acute myeloid leukaemia (AML) is needed to improve patients’ outcome. These features should be ideally present in many patients independently of mutational background. Here we identify de novo fatty acid (FA) desaturation, specifically stearoyl-CoA desaturase (SCD) inhibition, as a therapeutic vulnerability across multiple AML models in vitro and in vivo . SCD inhibition induces AML cell death via pleiotropic effects, and sensitivity is based on their dependency on FA desaturation regardless of mutational profile. Its efficacy is enhanced by driving FA biosynthesis in vitro and is less prominent in vivo due to stromal protection. SCD inhibition increases DNA damage and its combination with standard DNA damage-inducing chemotherapy prolongs survival in aggressive murine AML models. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their therapeutic potential. KEY POINTS ### Competing Interest Statement LH is CEO and co-founder of Modulation Therapeutics, the company holding intellectual property to SSI-4. J.A.C. holds a patent regarding use of the SCD inhibitor SSI-4.