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

Abstract

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 polypeptide (ELP) creates a gel-like depot upon subcutaneous injection that abolishes tumors in DRA-sensitive Colo205 mouse xenografts. Combination of ELPdepot-DRA with BCL-XL and/or XIAP inhibitors led to tumor growth inhibition and extended survival in DRA-resistant patient-derived xenografts. This strategy provides a precision medicine approach to overcome similar challenges with other protein-based cancer therapies.

• Authors: Mandana T Manzari, Gray 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, Ashutosh Chilkoti
• Journal: Science advances (Sci Adv) Vol. 5 Issue 9 Pg. eaaw9162 (09 2019) ISSN: 2375-2548 [Electronic] United States
• PMID: 31517048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BCL2L1 protein, human
• Delayed-Action Preparations
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• bcl-X Protein

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Delayed-Action Preparations (chemistry, pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• HCT116 Cells
• HT29 Cells
• Humans
• Mice
• X-Linked Inhibitor of Apoptosis Protein (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays
• bcl-X Protein (antagonists & inhibitors, genetics, metabolism)