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

Tom Nyen, Mélanie Planque, Lilian Wagensveld, Joao A. G. Duarte, Esther A. Zaal, Ali Talebi, Matteo Rossi, Pierre-René Körner, Lara Rizzotto, Stijn Moens, Wout 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 Lambrechts, Ben Davidson, Reuven Agami, Sarah-Maria Fendt, Daniela Annibali () and Frédéric Amant ()
Additional contact information
Tom Nyen: KU Leuven and Leuven Cancer Institute (LKI)
Mélanie Planque: VIB-KU Leuven Center for Cancer Biology, VIB
Lilian Wagensveld: Maastricht University Medical Centre
Joao A. G. Duarte: VIB-KU Leuven Center for Cancer Biology, VIB
Esther A. Zaal: Utrecht University
Ali Talebi: KU Leuven and Leuven Cancer Institute (LKI)
Matteo Rossi: VIB-KU Leuven Center for Cancer Biology, VIB
Pierre-René Körner: The Netherlands Cancer Institute
Lara Rizzotto: KU Leuven and Leuven Cancer Institute (LKI)
Stijn Moens: KU Leuven and Leuven Cancer Institute (LKI)
Wout Wispelaere: KU Leuven and Leuven Cancer Institute (LKI)
Regina E. M. Baiden-Amissah: KU Leuven and Leuven Cancer Institute (LKI)
Gabe S. Sonke: The Netherlands Cancer Institute
Hugo M. Horlings: The Netherlands Cancer Institute
Guy Eelen: KU Leuven and Leuven Cancer Institute (LKI)
Emanuele Berardi: KU Leuven
Johannes V. Swinnen: KU Leuven and Leuven Cancer Institute (LKI)
Celia R. Berkers: Utrecht University
Peter Carmeliet: KU Leuven and Leuven Cancer Institute (LKI)
Diether Lambrechts: KU Leuven
Ben Davidson: University of Oslo, Faculty of Medicine, Institute of Clinical Medicine
Reuven Agami: The Netherlands Cancer Institute
Sarah-Maria Fendt: VIB-KU Leuven Center for Cancer Biology, VIB
Daniela Annibali: KU Leuven and Leuven Cancer Institute (LKI)
Frédéric Amant: KU Leuven and Leuven Cancer Institute (LKI)

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32272-6

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