Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation

Author:

Dembitz VilmaORCID,Lawson Hannah,Burt Richard,Natani Sirisha,Philippe CélineORCID,James Sophie C.,Atkinson Samantha,Durko JozefORCID,Wang Lydia M.,Campos Joana,Magee Aoife M. S.,Woodley Keith,Austin Michael J.ORCID,Rio-Machin AnaORCID,Casado PedroORCID,Bewicke-Copley FindlayORCID,Rodriguez Blanco GiovannyORCID,Pereira-Martins Diego,Oudejans LieveORCID,Boet Emeline,von Kriegsheim Alex,Schwaller JuergORCID,Finch Andrew J.ORCID,Patel BelaORCID,Sarry Jean-EmmanuelORCID,Tamburini Jerome,Schuringa Jan Jacob,Hazlehurst Lori,Copland III John A.ORCID,Yuneva Mariia,Peck BarrieORCID,Cutillas PedroORCID,Fitzgibbon JudeORCID,Rouault-Pierre KevinORCID,Kranc KamilORCID,Gallipoli PaoloORCID

Abstract

AbstractIdentification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients’ outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. 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 full therapeutic potential.

Funder

Cancer Research UK

Lady Tata Memorial Trust

Publisher

Springer Science and Business Media LLC

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