Targeting G-quadruplex DNA to overcome resistance to PARP inhibitors

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PARP inhibitors such as Olaparib have revolutionised treatment of ovarian and breast cancers, whichare typically BRCA2 deficient. However, resistance to PARP inhibitors has been already observed inthe clinic, rising the need of alternative BRCA2-selective therapies. G-quadruplex ligands haverecently emerged as potential therapeutic tools that displayed increased toxicity in BRCA2 deficientgenetic backgrounds, retaining their activity also in Olaparib resistant cancers. However, there is alack of understanding of the fundamental biology linking PARP activity, NAD+ metabolism and Gquadruplex formation, which hampers to investigate further this therapeutic avenue. In this project, we propose to combine synthesis, metabolomics and genomics to unravel the crosstalk between PARP activity and G-quadruplex formation. This study, will shed light on the fundamentalmechanisms linking G-quadruplex formation and NAD+ metabolism, providing a platform for therational design of the next generation of drugs to treat PARP-resistant cancer patients.