Combined inhibition of receptor tyrosine and p21-activated kinases as a therapeutic strategy in childhood ALL

Ina Katrin Siekmann, Kevin Dierck, Sebastian Prall, Marianne Klokow, Julia Strauss, Sophia Buhs, Antonina Wrzeszcz, Michael Bockmayr, Florian Beck, Magdalena Trochimiuk, Kristina Gottschling, Victoria Martens, Melissa Khosh-Naucke, Helwe Gerull, Jürgen Müller, Lena Behrmann, Martin Blohm, René P. Zahedi, Irmela Jeremias, Albert SickmannPeter Nollau, Martin A. Horstmann* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Receptor tyrosine kinase (RTK)-dependent signaling has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) of childhood. However, the RTK-dependent signaling state and its interpretation with regard to biological behavior are often elusive. To decipher signaling circuits that link RTK activity with biological output in vivo, we established patient-derived xenograft ALL (PDX-ALL) models with dependencies on fms-like tyrosine kinase 3 (FLT3) and platelet-derived growth factor receptor b (PDGFRB), which were interrogated by phosphoproteomics using iTRAQ mass spectrometry. Signaling circuits were determined by receptor type and cellular context with few generic features, among which we identified group I p21-activated kinases (PAKs) as potential therapeutic targets. Growth factor stimulation markedly increased catalytic activities of PAK1 and PAK2. RNA interference (RNAi)-mediated or pharmacological inhibition of PAKs using allosteric or adenosine triphosphate (ATP)-competitive compounds attenuated cell growth and increased apoptosis in vitro. Notably, PAK1- or PAK2-directed RNAi enhanced the antiproliferative effects of the type III RTK and protein kinase C inhibitor midostaurin. Treatment of FLT3- or PDGFRB-dependent ALLs with ATP-competitive PAK inhibitors markedly decreased catalytic activities of both PAK isoforms. In FLT3-driven ALL, this effect was augmented by coadministration of midostaurin resulting in synergistic effects on growth inhibition and apoptosis. Finally, combined treatment of FLT3D835H PDX-ALL with the ATP-competitive group I PAK inhibitor FRAX486 and midostaurin in vivo significantly prolonged leukemia progression-free survival compared with midostaurin monotherapy or control. Our study establishes PAKs as potential downstream targets in RTK-dependent ALL of childhood, the inhibition of which might help prevent the selection or acquisition of resistance mutations toward tyrosine kinase inhibitors.

Original languageEnglish
Pages (from-to)2554-2567
Number of pages14
JournalBlood Advances
Issue number19
Publication statusPublished - 9 Oct 2018

Bibliographical note

Publisher Copyright:
© 2018 by The American Society of Hematology.

The authors thank Arne Düsedau (Heinrich Pette Institute) for flow cytometry sorting, Axel Leingärtner and Michael Horn-Glander for in vivo imaging (University Cancer Center Hamburg at Universitätsklinikum Hamburg-Eppendorf), and Dagmar Grabowski and Sonja Bartl (Department of Pediatric Oncology, University Medical Center Hamburg) for technical assistance.

This work was supported by Fördergemeinschaft Kinderkrebs–Zentrum Hamburg e.V., Madeleine Schickedanz KinderKrebsStiftung, Burkhard Meyer Stiftung and Ministerium für Kultur und Wissenschaft des Landes Nordrhein–Westfalen, Regierende Bürgermeister von Berlin–inkl. Wissenschaft und Forschung, and Bundesministerium für Bildung und Forschung. P.N. and A.S. received support from Bundesministerium für Bildung und Forschung for MedSys Project SARA 31P5800


  • Leukemia
  • lymphocytic
  • acute
  • childhood
  • midostaurin
  • ms-like tyrosine kinase 3
  • phosphotransferases
  • platelet-derived growth factor beta-receptor
  • receptor protein-tyrosine kinases
  • tyrosine
  • mass spectrometry
  • signal transduction
  • clinical trials and observations
  • lymphoid neoplasia


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