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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Manzari, MT; Anderson, GR; Lin, KH; Soderquist, RS; Çakir, M; Zhang, M; Moore, CE; Skelton, RN; Fèvre, M; Li, X; Bellucci, JJ; Wardell, SE; Costa, SA; Wood, KC; Chilkoti, A

Published Date

  • September 2019

Published In

Volume / Issue

  • 5 / 9

Start / End Page

  • eaaw9162 -

PubMed ID

  • 31517048

Pubmed Central ID

  • 31517048

Electronic International Standard Serial Number (EISSN)

  • 2375-2548

Digital Object Identifier (DOI)

  • 10.1126/sciadv.aaw9162

Language

  • eng

Conference Location

  • United States