2022-RA-953-ESGO Serine metabolism remodeling after platinum-based chemotherapy is a new vulnerability in resistant ovarian cancer patients

Abstract

<h3>Introduction/Background</h3> Resistance to platinum-based chemotherapy represents a major challenge for the management of many cancer patients, particularly those with epithelial ovarian cancer. Despite improved knowledge of the molecular determinants of platinum resistance, lack of clinical applicability still limits exploitation of many potential targets, leaving patients with limited options. Rewiring of cellular metabolism is now recognized as one of the hallmarks of cancer cells, and the ability of cancer cells to plastically change their use of nutrients and amino acids has been linked to cell adaptation to death signaling and survival. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer has not been investigated before. <h3>Methodology</h3> Phosphoglycerate dehydrogenase (PHGDH) expression has been determined in matched biopsies from ovarian cancer patients collected longitudinally at diagnosis and at relapse after platinum treatment. Metabolomic and molecular analyses have been performed on the isogenic ovarian cancer cell lines A2780 (wt/cis). Results have been confirmed in sensitive, resistant and matched ovarian cancer patient-derived xenograft (PDX) models and PDX-derived organoid cultures. <h3>Results</h3> We discovered 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. Consequently, combining carboplatin and PARP or NAD⁺-synthesis inhibitors is effective in resistant models showing decreased serine synthesis activity. <h3>Conclusion</h3> Our findings, accepted for publication in Nature Communications, have immediate and strong clinical applicability, because they identify alterations in serine and NAD+ metabolism as actionable vulnerabilities in a subgroup of platinum resistant ovarian cancers, and provide a rationale to test novel combinatorial therapeutic approaches to target resistance in these patients.