This study was designed to improve the delivery and therapeutic efficacy of extrinsic apoptotic pathway agonists in human CRC cells. We addressed this objective by (i) evaluating the potency of a multivalent DRA in a panel of CRC cell lines, (ii) performing a CRISPR-mediated knockout screen in DRA-resistant CRC cells to identify genetic drivers of DRA resistance and overcome resistance by combining DRA with sensitizers informed by the knockout screen, (iii) developing a DRA fusion to ELPs form a subcutaneously injectable gel depot for slow release of DRA into the circulation, and (iv) assessing the in vivo therapeutic efficacy of the ELPdepot-DRA formulation in combination with the best sensitizers.

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