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Mol Cancer Ther. 2017 Apr;16(4):705-716. doi: 10.1158/1535-7163.MCT-16-0616. Epub 2017 Jan 30.

Insulin-Mediated Signaling Facilitates Resistance to PDGFR Inhibition in Proneural hPDGFB-Driven Gliomas.

Almiron Bonnin DA1,2, Ran C1,2, Havrda MC1,2, Liu H1,2, Hitoshi Y1,2,3, Zhang Z1,2, Cheng C1,2,4, Ung M1,4, Israel MA5,2,6.

Author information

1
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
2
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
3
Department of Neurosurgery, Rosai Hospital, Kumamoto, Japan.
4
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
5
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; Mark.A.Israel@Dartmouth.edu.
6
Departments of Medicine and Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

Abstract

Despite abundant evidence implicating receptor tyrosine kinases (RTK), including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma (GBM), the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance. To study the resistance of proneural gliomas that are driven by a PDGFR-regulated pathway to targeted tyrosine kinase inhibitors, we utilized a mouse model of proneural glioma in which mice develop tumors that become resistant to PDGFR inhibition. We found that tumors resistant to PDGFR inhibition required the expression and activation of the insulin receptor (IR)/insulin growth-like factor receptor (IGF1R) for tumor cell proliferation and survival. Cotargeting IR/IGF1R and PDGFR decreased the emergence of resistant clones in vitro Our findings characterize a novel model of glioma recurrence that implicates the IR/IGF1R signaling axis in mediating the development of resistance to PDGFR inhibition and provide evidence that IR/IGF1R signaling is important in the recurrence of the proneural subtype of glioma in which PDGF/PDGFR is most commonly expressed at a high level. Mol Cancer Ther; 16(4); 705-16. ©2017 AACR.

PMID:
28138037
DOI:
10.1158/1535-7163.MCT-16-0616
[Indexed for MEDLINE]
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