SYK Targeting Represents a Potential Therapeutic Option for Relapsed Resistant Pediatric ETV6-RUNX1 B-Acute Lymphoblastic Leukemia Patients

Int J Mol Sci. 2019 Dec 7;20(24):6175. doi: 10.3390/ijms20246175.

Abstract

The presence of the chromosomal rearrangement t(12;21)(ETV6-RUNX1) in childhood B-acute lymphoblastic leukemia (B-ALL) is an independent predictor of favorable prognosis, however relapses still occur many years later after stopping therapy, and patients often display resistance to current treatments. Since spleen tyrosine kinase (SYK), a cytosolic nonreceptor tyrosine kinase interacting with immune receptors, has been previously associated with malignant transformation and cancer cell proliferation, we aimed to assess its role in ETV6-RUNX1 cell survival and prognosis. We evaluated the effects on cell survival of three SYK inhibitors and showed that all of them, in particular entospletinib, are able to induce cell death and enhance the efficacy of conventional chemotherapeutics. By using reverse phase protein arrays we next revealed that activated SYK is upregulated at diagnosis in pediatric ETV6-RUNX1 patients who will experience relapse, and, importantly, hyperactivation is maintained at a high level also at relapse occurrence. We thus treated primary cells from patients both at diagnosis and relapse with the combination entospletinib + chemotherapeutics and observed that SYK inhibition is able to sensitize resistant primary cells to conventional drugs. Entospletinib could thus represent a new therapeutic option supporting conventional chemotherapy for relapsed ETV6-RUNX1 patients, and these evidences encourage further studies on SYK for treatment of other relapsed resistant acute lymphoblastic leukemia (ALL) subgroups.

Keywords: SYK; entospletinib; leukemia; relapse.

MeSH terms

  • Aminopyridines
  • Cell Proliferation / drug effects
  • Child
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Cyclohexylamines / pharmacology
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Indazoles / pharmacology
  • Morpholines
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Oxazines / pharmacology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / pharmacology
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Syk Kinase / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • 2-(2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide
  • 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine
  • Aminopyridines
  • Core Binding Factor Alpha 2 Subunit
  • Cyclohexylamines
  • Indazoles
  • Morpholines
  • Oncogene Proteins, Fusion
  • Oxazines
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyridines
  • Pyrimidines
  • TEL-AML1 fusion protein
  • SYK protein, human
  • Syk Kinase
  • fostamatinib