title: Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma.
abstract: BACKGROUND
  Platelet-derived growth factor receptor A is altered by amplification and/or mutation in diffuse intrinsic pontine glioma (DIPG). We explored in vitro on new DIPG models the efficacy of dasatinib, a multi-tyrosine kinase inhibitor targeting this receptor.
  
  
  METHODS
  Gene expression profiles were generated from 41 DIPGs biopsied at diagnosis and compared with the signature associated with sensitivity/resistance to dasatinib. A panel of 12 new DIPG cell lines were established from biopsy at diagnosis, serially passaged, and characterized by gene expression analyses. Effects of dasatinib (1-10 μM) on proliferation, invasion, and cytotoxicity were determined on 4 of these cell lines using live-cell imaging and flow cytometry assays. Downstream signaling and receptor tyrosine kinases (RTKs) were assessed by western blot and phospho-RTK array. The effect of the combination with the c-Met inhibitor cabozantinib was studied on cellular growth and invasion analyzed by the Chou-Talaly method.
  
  
  RESULTS
  DIPG primary tumors and cell lines exhibited the gene expression signature of sensitivity to dasatinib. Dasatinib reduced proliferation (half-maximal inhibitory concentration = 10-100 nM) and invasion (30%-60% reduction) at 100 nM in 4/4 cultures and induced apoptosis in 1 of 4 DIPG cell lines. Activity of downstream effectors of dasatinib targets including activin receptor 1 was strongly reduced. Since multiple RTKs were activated simultaneously in DIPG cell lines, including c-Met, which can be also amplified in DIPG, the benefit of the combination of dasatinib with cabozantinib was explored for its synergistic effects on proliferation and migration/invasion in these cell lines.
  
  
  CONCLUSIONS
  Dasatinib exhibits antitumor effects in vitro that could be increased by the combination with another RTK inhibitor targeting c-Met.
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Nathalène
authors.initials: N
authors.lastname: Truffaux
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Cathy
authors.initials: C
authors.lastname: Philippe
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Janna
authors.initials: J
authors.lastname: Paulsson
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Felipe
authors.initials: F
authors.lastname: Andreiuolo
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Léa
authors.initials: L
authors.lastname: Guerrini-Rousseau
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Gaétan
authors.initials: G
authors.lastname: Cornilleau
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Ludivine
authors.initials: L
authors.lastname: Le Dret
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Richon
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Puget
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.affiliation: CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (N.T., C.P., F.A., L.G.-R., G.C., L.L.-D., B.G., G.V., J.G.); Functional Genomics Unit, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (C.R.); Translational Research Laboratory and Biobank, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Inserm U981, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Medical Biology and Pathology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (L.L.); Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Paris XI University, Villejuif, France (B.G., J.G.); Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden (J.P., A.Ö.); Department of Neurosurgery, Necker-Sick Children Hospital, Paris Descartes University, Paris, France (S.P.).
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
mesh_terms: D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D020295:Brain Stem Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D000069439:Dasatinib / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011149:Pons / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D019859:Proto-Oncogene Proteins c-met; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000069439:Dasatinib
keywords: ACVR1; PDGFRA; Src; brainstem; preclinical model