Determinants of Sensitivity to G-Quadruplex-Binding Compounds

The observation that BRCA1 and BRCA2 deficient cells and tumours are sensitive to G-quadruplex (G4) ligands has spurred development of cancer therapies using these molecules to target homologous recombination deficiencies. The cytotoxicity of these drugs relies on binding and stabilisation of G4 structures. These, in turn, block replication fork progression and induce DNA breakage (Rodriguez et al., 2012; Zimmer et al., 2016). The precise type of DNA lesions and signalling pathways triggered by G4 ligands remain unclear. Here we propose to perform a CRISPR/Cas9 screen in human cells to identify determinants of sensitivity to G4-binding compounds. We will focus on CX-5461, a G4 ligand currently in clinical trials against tumours with DNA repair deficient tumours, including those carrying BRCA1/2 mutations (Xu et al., 2017). We aim to identify a set of genes whose targeting leads to sensitivity or resistance to CX-5461 treatment. Through functional characterization of these genes, we will assemble a profile of the pathways de-regulated by this drug and how they impact on cell proliferation and survival. This approach will not only help elucidate the mechanism of action of CX-5461, but will also enable to predict tumour response and select patients likely to benefit from this specialised therapy. 

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