Identification of drug resistance mechanisms and acquired sensitivities in resistant cancer cells using genome-wide CRISPR-mediated screens

Multidrug resistance is a major issue in the cancer field. To counter this problem, extensive research unravelling the molecular mechanisms underlying multidrug resistance is highly needed. This enables the discovery of biomarkers and facilitates the identification of novel drug targets. For this purpose, genome-wide CRISPR screens, based on gene activation and gene knock-out, will be implemented. In this way, resistance mechanisms to specific drugs, such as selinexor and imatinib, can be identified. Moreover, in addition to the commonly studied coding resistance mechanisms, non-coding resistance mechanisms will be investigated by using non-coding CRISPR libraries. It is also known that drug resistant cancer cells sometimes can become hypersensitive to specific drugs, compared to their non-resistant counterparts. This is referred to as collateral sensitivity. By performing CRISPR knock-out screens, such collateral sensitivities will be identified. Specifically, in this project, collateral sensitivities in ABC transporter hyperactive cancer cells and cancer cells that depend on the ALT-pathway will be investigated. Clinically relevant and druggable vulnerabilities discovered in this project will then subsequently be targeted in novel combination therapies.