Combined inhibition of receptor tyrosine and p21-activated kinases as a therapeutic strategy in childhood ALL.
Blood Adv, 2018/10/09;2(19):2554-2567.
Siekmann IK[1, 2], Dierck K[1, 2], Prall S[1, 2], Klokow M[1, 2], Strauss J[1, 2], Buhs S[1, 2], Wrzeszcz A[1, 2], Bockmayr M[1, 2, 3], Beck F[4], Trochimiuk M[1, 2], Gottschling K[1, 2], Martens V[1, 2], Khosh-Naucke M[1, 2], Gerull H[1, 2], Müller J[1, 2], Behrmann L[1, 2], Blohm M[5], Zahedi RP[4, 6, 7], Jeremias I[8], Sickmann A[4, 9, 10], Nollau P[1, 2], Horstmann MA[1, 2]
Affiliations
PMID: 30301811DOI: 10.1182/bloodadvances.2018020693
Impact factor: 7.637
Abstract
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 β (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 FLT3 D835H 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.
MeSH terms
Animals; Antineoplastic Agents; Cell Line, Tumor; Child; Disease Models, Animal; Gene Expression Regulation, Leukemic; Humans; Lymphopoiesis; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteome; Treatment Outcome; Xenograft Model Antitumor Assays; p21-Activated Kinases
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