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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers

Combined Cellular and Biochemical Profiling to Identify Predictive Drug Response Biomarkers for Kinase Inhibitors Approved for Clinical Use between 2013 and 2017

Joost C.M. Uitdehaag, Jeffrey J. Kooijman, Jeroen A.D.M. de Roos, Martine B.W. Prinsen, Jelle Dylus, Nicole Willemsen-Seegers, Yusuke Kawase, Masaaki Sawa, Jos de Man, Suzanne J.C. van Gerwen, Rogier C. Buijsman and Guido J.R. Zaman
Joost C.M. Uitdehaag
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Jeffrey J. Kooijman
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Jeroen A.D.M. de Roos
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Martine B.W. Prinsen
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Jelle Dylus
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Nicole Willemsen-Seegers
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Yusuke Kawase
2Carna Biosciences, Inc., Kobe, Japan.
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Masaaki Sawa
2Carna Biosciences, Inc., Kobe, Japan.
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  • ORCID record for Masaaki Sawa
Jos de Man
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Suzanne J.C. van Gerwen
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Rogier C. Buijsman
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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Guido J.R. Zaman
1Netherlands Translational Research Center B.V., Oss, the Netherlands.
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  • For correspondence: guido.zaman@ntrc.nl
DOI: 10.1158/1535-7163.MCT-18-0877 Published February 2019
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Abstract

Kinase inhibitors form the largest class of precision medicine. From 2013 to 2017, 17 have been approved, with 8 different mechanisms. We present a comprehensive profiling study of all 17 inhibitors on a biochemical assay panel of 280 kinases and proliferation assays of 108 cancer cell lines. Drug responses of the cell lines were related to the presence of frequently recurring point mutations, insertions, deletions, and amplifications in 15 well-known oncogenes and tumor-suppressor genes. In addition, drug responses were correlated with basal gene expression levels with a focus on 383 clinically actionable genes. Cell lines harboring actionable mutations defined in the FDA labels, such as mutant BRAF(V600E) for cobimetinib, or ALK gene translocation for ALK inhibitors, are generally 10 times more sensitive compared with wild-type cell lines. This sensitivity window is more narrow for markers that failed to meet endpoints in clinical trials, for instance CDKN2A loss for CDK4/6 inhibitors (2.7-fold) and KRAS mutation for cobimetinib (2.3-fold). Our data underscore the rationale of a number of recently opened clinical trials, such as ibrutinib in ERBB2- or ERBB4-expressing cancers. We propose and validate new response biomarkers, such as mutation in FBXW7 or SMAD4 for EGFR and HER2 inhibitors, ETV4 and ETV5 expression for MEK inhibitors, and JAK3 expression for ALK inhibitors. Potentially, these new markers could be combined to improve response rates. This comprehensive overview of biochemical and cellular selectivities of approved kinase inhibitor drugs provides a rich resource for drug repurposing, basket trial design, and basic cancer research.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received August 3, 2018.
  • Revision received September 17, 2018.
  • Accepted October 23, 2018.
  • Published first October 31, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (2)
February 2019
Volume 18, Issue 2
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Combined Cellular and Biochemical Profiling to Identify Predictive Drug Response Biomarkers for Kinase Inhibitors Approved for Clinical Use between 2013 and 2017
Joost C.M. Uitdehaag, Jeffrey J. Kooijman, Jeroen A.D.M. de Roos, Martine B.W. Prinsen, Jelle Dylus, Nicole Willemsen-Seegers, Yusuke Kawase, Masaaki Sawa, Jos de Man, Suzanne J.C. van Gerwen, Rogier C. Buijsman and Guido J.R. Zaman
Mol Cancer Ther February 1 2019 (18) (2) 470-481; DOI: 10.1158/1535-7163.MCT-18-0877

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Combined Cellular and Biochemical Profiling to Identify Predictive Drug Response Biomarkers for Kinase Inhibitors Approved for Clinical Use between 2013 and 2017
Joost C.M. Uitdehaag, Jeffrey J. Kooijman, Jeroen A.D.M. de Roos, Martine B.W. Prinsen, Jelle Dylus, Nicole Willemsen-Seegers, Yusuke Kawase, Masaaki Sawa, Jos de Man, Suzanne J.C. van Gerwen, Rogier C. Buijsman and Guido J.R. Zaman
Mol Cancer Ther February 1 2019 (18) (2) 470-481; DOI: 10.1158/1535-7163.MCT-18-0877
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Molecular Cancer Therapeutics
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