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Updated: Sep 2, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant
Tom Van Nyen1,2, Mélanie Planque3,4, Lilian van Wagensveld5,6,7
1Gynecological Oncology Laboratory, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000, Leuven, Belgium.
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.
Insights
Platinum-resistant ovarian cancer may be vulnerable. Some resistant tumors show decreased phosphoglycerate dehydrogenase (PHGDH), aiding cancer cell survival by regenerating NAD+ to sustain PARP activity.
Area of Science:
- Biochemistry
- Oncology
- Metabolic pathways
Background:
- Platinum-based chemotherapy is a cornerstone treatment for epithelial ovarian cancer.
- Tumor resistance to platinum chemotherapy is a significant clinical challenge, leading to poor patient outcomes.
- The role of serine biosynthesis in platinum-resistant ovarian cancer remains largely unexplored.
Purpose of the Study:
- To investigate the role of serine biosynthesis in platinum-resistant ovarian cancer.
- To identify potential metabolic vulnerabilities in tumors that develop resistance to platinum-based chemotherapy.
Main Methods:
- Analysis of phosphoglycerate dehydrogenase (PHGDH) expression in platinum-resistant ovarian tumors.
- Investigation of nicotinamide adenine dinucleotide (NAD+) regeneration pathways.
- Assessment of Poly (ADP-ribose) polymerase (PARP) activity in resistant cancer cells.
Main Results:
- A subset of platinum-resistant ovarian tumors exhibited decreased PHGDH expression upon relapse.
- This decrease in PHGDH was associated with an enhanced NAD+ regeneration phenotype.
- The NAD+ regeneration supported sustained PARP activity, contributing to platinum resistance.
Conclusions:
- Reduced PHGDH expression is a metabolic adaptation in a subgroup of platinum-resistant ovarian cancers.
- Targeting serine biosynthesis or NAD+ metabolism may offer therapeutic strategies for overcoming platinum resistance.
- These findings highlight metabolic vulnerabilities with potential clinical implications for ovarian cancer treatment.
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