GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide.

Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients.

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Copyright © 2022 Parik, Fernández-García, Lodi, De Vlaminck, Derweduwe, De Vleeschouwer, Sciot, Geens, Weng, Bosisio, Bergers, Duerinck, De Smet, Lambrechts, Van Ginderachter and Fendt.

Déclaration de conflit d'intérêts

S-MF has received funding from Bayer AG, Merck and Black Belt Therapeutics, has consulted for Fund+ and is in the advisory board of Alesta Therapeutics. JVG collaborates with Montis and has consulted for Fund+. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.