Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers

Tom van Nyen, M. lanie Planque, Lilian van Wagensveld, Joao A. G. Duarte, Esther A. Zaal, Ali Talebi, Matteo Rossi, Pierre-René Körner, Lara Rizzotto, Stijn Moens, Wout de Wispelaere, Regina E. M. Baiden-Amissah, Gabe S. Sonke, Hugo M. Horlings, Guy Eelen, Emanuele Berardi, Johannes V. Swinnen, Celia R. Berkers, Peter Carmeliet, Diether LambrechtsBen Davidson, Reuven Agami, Sarah-Maria Fendt, Daniela Annibali, Frédéric Amant

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12–15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers.
Original languageEnglish
Article number4578
JournalNature communications
Volume13
Issue number1
DOIs
Publication statusPublished - 1 Dec 2022

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