The cyclin-G associated kinase (GAK) is a clinically actionable drug target required for mitosis in diffuse large B-cell lymphoma

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Abstract
Though 100 kinase inhibitors are approved for clinical use, most kinases in the genome remain poorly characterized. Moreover, though kinase inhibitors have revolutionized the care of selected cancers, most others respond transiently or not at all to these drugs, typically directed against signal-transduction pathways. Given cellular regulation at every step by phosphorylation events, we hypothesized that phenotypic screening and machine-learning analysis can reveal novel kinase targets. Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, responds poorly to signal transduction-directed kinase inhibitors. We applied a library of probes to DLBCL systems broadly representing its pathogenic heterogeneity and subjected results to iterative target-deconvolution analysis aimed at tumor selectivity (idTRAX). These efforts identified the cyclin G-associated kinase (GAK) as a tumor-selective target. Mechanistic studies showed GAK kinase activity is required for mitotic progression, with inhibition leading to G2/M arrest and cell death and increased efficacy in the absence of the retinoblastoma (RB) tumor suppressor. GAK-directed kinase inhibitors, including repurposed clinical compounds, showed promising single-agent anti-DLBCL activity in vivo. GAK kinase function is therefore a targetable dependency, opening novel treatment strategies suitable for rapid clinical translation. Moreover, we establish phenotypic screening with target deconvolution as a generalizable strategy to reveal tumor-selective kinase dependencies.
Funding Information
  • National Cancer Institute (R01CA296318)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (R01CA296318)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (R01CA296318)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (R01CA296318)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (R01CA296318)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (R01CA296318)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (P30CA240139)
  • National Cancer Institute (R01CA296318)
  • National Cancer Institute (P30CA240139)

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