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[Chemotaxis in cancer] – Metabolic vulnerability of cisplatin-resistant cancers. - Published on 21 08 2018
2018 Jul 13;37(14). pii: e98597. doi: 10.15252/embj.201798597. Epub 2018 Jun 6.

Obrist F1,2,3,4,5,6, Michels J1,2,3,4,5,6,7, Durand S2,3,4,5,6, Chery A2,3,4,5,6, Pol J2,3,4,5,6, Levesque S1,2,3,4,5,6, Joseph A2,3,4,5,6, Astesana V2,3,4,5,6,8, Pietrocola F2,3,4,5,6, Wu GS9, Castedo M10,3,4,5,6, Kroemer G10,3,4,5,6,11,12.

Abstract

Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancerand ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.

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This French program is organized by ITMO Cancer, in collaboration with ITMO BCDE (Cell Biology, Development and Evolution) and ITMO Technologies for Health of the National Alliance for Life Sciences and Health (AVIESAN) with the National Cancer Institute (INCA) and Inserm within the framework of the Cancer Plan. Operational management is entrusted to Inserm.
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