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Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor …

SCIENCE ADVANCES. 2019;

Mandana T. Manzari, Grace R. Anderson, Kevin H. Lin, Ryan S. Soderquist, Merve Çakir, Mitchell Zhang, Chandler E. Moore, Rachel N. Skelton, Maréva Fèvre, Xinghai Li, Joseph J. Bellucci, Suzanne E. Wardell, Simone A. Costa, Kris C. Wood and Ashutosh Chilkoti

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摘要

Extrinsic pathway agonists have failed repeatedly in the clinic for three core reasons: Inefficient ligand-induced receptor multimerization, poor pharmacokinetic properties, and tumor intrinsic resistance. Here, we address these factors by (i) using a highly potent death receptor agonist (DRA), (ii) developing an injectable depot for sustained DRA delivery, and (iii) leveraging a CRISPR-Cas9 knockout screen in DRA-resistant colorectal cancer (CRC) cells to identify functional drivers of resistance. Pharmacological blockade of XIAP and BCL-XL by targeted small-molecule drugs strongly enhanced the antitumor activity of DRA in CRC cell lines. Recombinant fusion of the DRA to a thermally responsive elastin-like po... More