Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy

Jacob I. Contreras, Caroline M. Robb, Hannah M. King, Jared Baxter, Ayrianne J. Crawford, Smit Kour, Smitha Kizhake, Yogesh A. Sonawane, Sandeep Rana, Michael A Hollingsworth, Xu Luo, Amarnath Natarajan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The study presented here provides a framework for the discovery of unique inhibitor combinations that target the apoptosis network for cancer therapy. A pair of doxycycline (Dox)-inducible cell lines that specifically report on the ability of an inhibitor to induce apoptosis by targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm were used. Cell-based assays were optimized for high throughput screening (HTS) with caspase 3/7 as a read out. HTS with a 355-member kinase inhibitor library and the panel of Dox-inducible cell lines revealed that cyclin dependent kinase (CDK) inhibitors induced apoptosis by targeting the Mcl-1 arm, whereas PI3K inhibitors induced apoptosis by targeting the Bcl-2/Bcl-xL/Bcl-w arm. Validation studies identified unique combinations that synergistically inhibited growth and induced apoptosis in a panel of cancer cell lines. Since these inhibitors have been or are currently in clinical trials as single agents, the combinations can be rapidly translated to the clinics.

Original languageEnglish (US)
Pages (from-to)1148-1152
Number of pages5
JournalACS Chemical Biology
Volume13
Issue number5
DOIs
StatePublished - May 18 2018

Fingerprint

Apoptosis Regulatory Proteins
Phosphotransferases
Apoptosis
Doxycycline
Cells
Neoplasms
Cell Line
Screening
Throughput
Caspase 7
Therapeutics
Cyclin-Dependent Kinases
Validation Studies
Phosphatidylinositol 3-Kinases
Caspase 3
Libraries
Assays
Clinical Trials
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy. / Contreras, Jacob I.; Robb, Caroline M.; King, Hannah M.; Baxter, Jared; Crawford, Ayrianne J.; Kour, Smit; Kizhake, Smitha; Sonawane, Yogesh A.; Rana, Sandeep; Hollingsworth, Michael A; Luo, Xu; Natarajan, Amarnath.

In: ACS Chemical Biology, Vol. 13, No. 5, 18.05.2018, p. 1148-1152.

Research output: Contribution to journalArticle

Contreras, Jacob I. ; Robb, Caroline M. ; King, Hannah M. ; Baxter, Jared ; Crawford, Ayrianne J. ; Kour, Smit ; Kizhake, Smitha ; Sonawane, Yogesh A. ; Rana, Sandeep ; Hollingsworth, Michael A ; Luo, Xu ; Natarajan, Amarnath. / Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy. In: ACS Chemical Biology. 2018 ; Vol. 13, No. 5. pp. 1148-1152.
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