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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Research Article

Target identification in small cell lung cancer via integrated phenotypic screening and activity-based protein profiling

Jiannong Li, Bin Fang, Fumi Kinose, Yun Bai, Jae-Young Kim, Yian Ann Chen, Uwe Rix, John M. Koomen and Eric B Haura
Jiannong Li
1Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute
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Bin Fang
2Proteomics Core Facility, Moffitt Cancer Center & Research Institute
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Fumi Kinose
1Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute
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Yun Bai
3Thoracic Oncology and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute
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Jae-Young Kim
4Thoracic Oncology, H Lee Moffitt Cancer Center and Research Insitute
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Yian Ann Chen
5Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute
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Uwe Rix
6Drug Discovery, H Lee Moffitt Cancer Center and Research Institute
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John M. Koomen
7Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute
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Eric B Haura
3Thoracic Oncology and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute
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  • For correspondence: eric.haura@moffitt.org
DOI: 10.1158/1535-7163.MCT-15-0444
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Abstract

To overcome hurdles in identifying key kinases in small cell lung cancer (SCLC), we integrated a target-agnostic phenotypic screen of kinase inhibitors with target identification using activity-based protein profiling (ABPP) in which a desthiobiotin-ATP probe was used. We screened 21 SCLC cell lines with known c-MYC amplification status for alterations in viability using a chemical library of 235 small molecule kinase inhibitors. One screen hit compound was interrogated with ABPP, and through this approach we re-identified aurora kinase B as a critical kinase in MYC-amplified SCLC cells. We next extended the platform to a second compound that had activity in SCLC cell lines lacking c-MYC amplification and identified TANK-binding kinase 1 (TBK1), a kinase that affects cell viability, polo-like kinase-1 signaling, G2/M arrest, and apoptosis in SCLC cells lacking MYC amplification. These results demonstrate that phenotypic screening combined with activity-based protein profiling can identify key disease drivers, suggesting that this approach, which combines new chemical probes and disease cell screens, has the potential to identify other important targets in other cancer types.

  • Received June 2, 2015.
  • Revision received October 14, 2015.
  • Accepted November 30, 2015.
  • Copyright © 2016, American Association for Cancer Research.
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This OnlineFirst version was published on January 15, 2016
doi: 10.1158/1535-7163.MCT-15-0444

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Target identification in small cell lung cancer via integrated phenotypic screening and activity-based protein profiling
Jiannong Li, Bin Fang, Fumi Kinose, Yun Bai, Jae-Young Kim, Yian Ann Chen, Uwe Rix, John M. Koomen and Eric B Haura
Mol Cancer Ther January 15 2016 DOI: 10.1158/1535-7163.MCT-15-0444

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Target identification in small cell lung cancer via integrated phenotypic screening and activity-based protein profiling
Jiannong Li, Bin Fang, Fumi Kinose, Yun Bai, Jae-Young Kim, Yian Ann Chen, Uwe Rix, John M. Koomen and Eric B Haura
Mol Cancer Ther January 15 2016 DOI: 10.1158/1535-7163.MCT-15-0444
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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