ENCORE_Pilot__New_Targets_for_Effective_Combination_Therapies_in_Tumors_with_Unmet_Medical_Need
Many cancer patients have tumours with resistance to standard of care therapy or have a molecular context that is not addressed by current treatments. Combination therapies aimed at inhibiting multiple targets or cancer pathways can combat resistance and exploit new actionable dependencies in defined genetic contexts. Critically, the number of possible combinations for target/pathway inhibition is prohibitively large and we are limited in our ability to predict which combinations of targets are likely to be effective in which patients. We propose to unlock the potential of rational target/pathway combinations in oncology through an ambitious integrative network biology and functional genomics approach utilising large-scale two-gene combinatorial CRISPR (2G-CRISPR) knock-out screens. We will focus on KRAS-mutant colon and triplenegative breast cancers, two cancer types with unmet clinical need with preclinical models available for screening. We aim to identify pathway synergies in these defined genetic contexts which will be integrated into high density network maps of combination response to inform on mechanism. Overall, this project will provide new targets whose inhibition will be effective in combination in the setting of primary or secondary drug resistance.