A PDGFR-driven mouse model of Glioblastoma reveals a Stathmin1-mediated mechanism of sensitivity to Vinblastine

Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFR and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of PDGFR and the analysis of GBM signaling pathways using proteomics. We discovered the tubulin-binding protein Stathmin1 (STMN1) as a PDGFR phospho-regulated target and that this mis-regulation conferred selective sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFR GBMs with VB in mice drastically prolonged survival and was dependent on STMN1. Our work provides a rationale for evaluating genotype-specific anti-microtubule drugs as cancer treatment in select GBM patient populations.

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Jun HJ, Appleman VA, Wu HJ, Rose CM, Pineda JJ, Yeo AT, Delcuze B, Lee C, Gyuris A, Zhu H, Woolfenden S, Bronisz A, Nakano I, Chiocca EA, Bronson RT, Ligon KL, Sarkaria JN, Gygi SP, Michor F, Mitchison TJ, Charest A