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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 models.

Publication ,  Journal Article
Manzari, MT; Anderson, GR; Lin, KH; Soderquist, RS; Çakir, M; Zhang, M; Moore, CE; Skelton, RN; Fèvre, M; Li, X; Bellucci, JJ; Wardell, SE ...
Published in: Sci Adv
September 2019

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.

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Published In

Sci Adv

DOI

EISSN

2375-2548

Publication Date

September 2019

Volume

5

Issue

9

Start / End Page

eaaw9162

Location

United States

Related Subject Headings

  • bcl-X Protein
  • Xenograft Model Antitumor Assays
  • X-Linked Inhibitor of Apoptosis Protein
  • Mice
  • Humans
  • HT29 Cells
  • HCT116 Cells
  • Drug Resistance, Neoplasm
  • Delayed-Action Preparations
  • Colorectal Neoplasms
 

Citation

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MLA
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Manzari, M. T., Anderson, G. R., Lin, K. H., Soderquist, R. S., Çakir, M., Zhang, M., … Chilkoti, A. (2019). Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models. Sci Adv, 5(9), eaaw9162. https://doi.org/10.1126/sciadv.aaw9162
Manzari, Mandana T., Gray R. Anderson, Kevin H. Lin, Ryan S. Soderquist, Merve Çakir, Mitchell Zhang, Chandler E. Moore, et al. “Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models.Sci Adv 5, no. 9 (September 2019): eaaw9162. https://doi.org/10.1126/sciadv.aaw9162.
Manzari, Mandana T., et al. “Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models.Sci Adv, vol. 5, no. 9, Sept. 2019, p. eaaw9162. Pubmed, doi:10.1126/sciadv.aaw9162.
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. Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models. Sci Adv. 2019 Sep;5(9):eaaw9162.

Published In

Sci Adv

DOI

EISSN

2375-2548

Publication Date

September 2019

Volume

5

Issue

9

Start / End Page

eaaw9162

Location

United States

Related Subject Headings

  • bcl-X Protein
  • Xenograft Model Antitumor Assays
  • X-Linked Inhibitor of Apoptosis Protein
  • Mice
  • Humans
  • HT29 Cells
  • HCT116 Cells
  • Drug Resistance, Neoplasm
  • Delayed-Action Preparations
  • Colorectal Neoplasms