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

Mandana T. Manzari | Zendy; Grace R. Anderson | Zendy; Kevin Lin | Zendy; Ryan S. Soderquist | Zendy; Merve Çakır | Zendy; Mitchel Zhang | Zendy; Chandler E. Moore | Zendy; Rachel N. Skelton | Zendy; M. Fèvre | Zendy; Xinghai Li | Zendy; Joseph J. Bellucci | Zendy; Suzanne E. Wardell | Zendy; Simone A. Costa | Zendy; Kris C. Wood | Zendy; Ashutosh Chilkoti | Zendy

Open Access

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

Author(s) -

Mandana T. Manzari,

Grace R. Anderson,

Kevin Lin,

Ryan S. Soderquist,

Merve Çakır,

Mitchel Zhang,

Chandler E. Moore,

Rachel N. Skelton,

M. Fèvre,

Xinghai Li,

Joseph J. Bellucci,

Suzanne E. Wardell,

Simone A. Costa,

Kris C. Wood,

Ashutosh Chilkoti

Publication year - 2019

Publication title -

science advances

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.928

H-Index - 146

ISSN - 2375-2548

DOI - 10.1126/sciadv.aaw9162

Subject(s) - agonist , receptor , pharmacology , medicine , small molecule , bioinformatics , chemistry , biology , biochemistry

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-X 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 ELP-DRA with BCL-X 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.

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