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Decreased serine biosynthesis identifies a subgroup of platinum resistant ovarian cancers and novel actionable metabolic vulnerabilities

ABSTRACT: Decreased serine biosynthesis identifies a subgroup of platinum resistant ovarian cancers and novel actionable metabolic vulnerabilities

PROVIDER: PRJNA735397 | ENA |

REPOSITORIES: ENA

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Decreased serine biosynthesis identifies a subgroup of platinum resistant ovarian cancers and novel actionable metabolic vulnerabilities

Project description:Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, particularly epithelial ovarian cancer. After initial response, patients often experience several response-relapse events, until tumors start to resist the treatment. Resistant patients have low response rate to other chemotherapy regimens, with life expectancy of 12-15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, and no novel drugs have been approved for resistant disease. By investigating the functional link between metabolic adaptations and resistance, we discovered that resistant cells modify their serine metabolism and acquire a specific NAD+ generating phenotype, which allows them to sustain PARP activity under treatment. Our findings reveal a novel metabolic vulnerability of resistant tumors that might have an immediate clinical implication, showing that ex vivo patient derived resistant models can be re-sensitized to platinum by combining it with PARP inhibition.

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Project description:Resistance to platinum-based chemotherapy is a clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, innovative drugs against platinum-resistance are urgently needed. Our therapeutic concept is based on the conjugation of two chemotherapeutic compounds to a monotherapeutic pro-drug, which is taken up by cancer cells and cleaved into active cytostatic metabolites. Here, we explore the activity of the duplex-prodrug 5-FdU-ECyd, covalently linking 2'-deoxy-5-fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), on platinum-resistant OC cells. RNA-Sequencing was used for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis.

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