Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Autor:	Eyme KM; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA.; Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany., Sammarco A; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA.; Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy.; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA., Jha R; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA., Mnatsakanyan H; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA., Pechdimaljian C; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA., Carvalho L; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA.; Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA., Neustadt R; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA., Moses C; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA., Alnasser A; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA., Tardiff DF; Yumanity Therapeutics, Boston, MA 02139, USA., Su B; Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.; UCLA Lipidomics Laboratory, University of California, Los Angeles, CA 90095, USA., Williams KJ; Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.; UCLA Lipidomics Laboratory, University of California, Los Angeles, CA 90095, USA., Bensinger SJ; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.; UCLA Lipidomics Laboratory, University of California, Los Angeles, CA 90095, USA., Chung CY; Yumanity Therapeutics, Boston, MA 02139, USA., Badr CE; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA.; Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2023 Jan 18; Vol. 15 (679), pp. eabq6288. Date of Electronic Publication: 2023 Jan 18.
DOI:	10.1126/scitranslmed.abq6288
Abstrakt:	Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.
Databáze:	MEDLINE
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