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Neuro Oncol. 2015 Jul;17(7):953-64. doi: 10.1093/neuonc/nou330. Epub 2014 Dec 21.

Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma.

Author information

1
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.).

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.

CONCLUSION:

Dasatinib exhibits antitumor effects in vitro that could be increased by the combination with another RTK inhibitor targeting c-Met.

KEYWORDS:

ACVR1; PDGFRA; Src; brainstem; preclinical model

PMID:
25534822
PMCID:
PMC5654348
DOI:
10.1093/neuonc/nou330
[Indexed for MEDLINE]
Free PMC Article

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