title: Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening.
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.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Wayne F
authors.initials: WF
authors.lastname: Yang
authors.forename: Armand
authors.initials: A
authors.lastname: Bankhead
authors.forename: Guang
authors.initials: G
authors.lastname: Fan
authors.forename: Luke B
authors.initials: LB
authors.lastname: Fletcher
authors.forename: Jade
authors.initials: J
authors.lastname: Bryant
authors.forename: Jason M
authors.initials: JM
authors.lastname: Glover
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Spurgeon
authors.forename: William H
authors.initials: WH
authors.lastname: Fleming
authors.forename: Tibor
authors.initials: T
authors.lastname: Kovacsovics
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gotlib
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Oh
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.forename: Christian Michel
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Monique L
authors.initials: ML
authors.lastname: Den Boer
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
mesh_terms: D000465:Algorithms; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D011505:Protein-Tyrosine Kinases