Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening

Jeffrey Tyner, Wayne F. Yang, Armand Bankhead, Guang Fan, Luke B. Fletcher, Jade Bryant, Jason M. Glover, Bill Chang, Stephen Spurgeon, William Fleming, Tibor Kovacsovics, Jason R. Gotlib, Stephen T. Oh, Michael W. Deininger, Christian Michel Zwaan, Monique L. Den Boer, Marry M. Van Den Heuvel-Eibrink, Thomas O'Hare, Brian Druker, Marc Loriaux

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options.

Original languageEnglish (US)
Pages (from-to)285-296
Number of pages12
JournalCancer Research
Volume73
Issue number1
DOIs
StatePublished - Jan 1 2013

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Leukemia
Phosphotransferases
Pharmaceutical Preparations
High-Throughput Nucleotide Sequencing
Mutation
Molecular Pathology
Oncogenes
Routine Diagnostic Tests
Drug Resistance
Neoplasms
Hypersensitivity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening. / Tyner, Jeffrey; Yang, Wayne F.; Bankhead, Armand; Fan, Guang; Fletcher, Luke B.; Bryant, Jade; Glover, Jason M.; Chang, Bill; Spurgeon, Stephen; Fleming, William; Kovacsovics, Tibor; Gotlib, Jason R.; Oh, Stephen T.; Deininger, Michael W.; Zwaan, Christian Michel; Den Boer, Monique L.; Van Den Heuvel-Eibrink, Marry M.; O'Hare, Thomas; Druker, Brian; Loriaux, Marc.

In: Cancer Research, Vol. 73, No. 1, 01.01.2013, p. 285-296.

Research output: Contribution to journalArticle

Tyner, J, Yang, WF, Bankhead, A, Fan, G, Fletcher, LB, Bryant, J, Glover, JM, Chang, B, Spurgeon, S, Fleming, W, Kovacsovics, T, Gotlib, JR, Oh, ST, Deininger, MW, Zwaan, CM, Den Boer, ML, Van Den Heuvel-Eibrink, MM, O'Hare, T, Druker, B & Loriaux, M 2013, 'Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening', Cancer Research, vol. 73, no. 1, pp. 285-296. https://doi.org/10.1158/0008-5472.CAN-12-1906
Tyner, Jeffrey ; Yang, Wayne F. ; Bankhead, Armand ; Fan, Guang ; Fletcher, Luke B. ; Bryant, Jade ; Glover, Jason M. ; Chang, Bill ; Spurgeon, Stephen ; Fleming, William ; Kovacsovics, Tibor ; Gotlib, Jason R. ; Oh, Stephen T. ; Deininger, Michael W. ; Zwaan, Christian Michel ; Den Boer, Monique L. ; Van Den Heuvel-Eibrink, Marry M. ; O'Hare, Thomas ; Druker, Brian ; Loriaux, Marc. / Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening. In: Cancer Research. 2013 ; Vol. 73, No. 1. pp. 285-296.
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