P16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells

Ling Cen, Brett L. Carlson, Mark A. Schroeder, Jamie L. Ostrem, Gaspar J. Kitange, Ann C. Mladek, Stephanie R. Fink, Paul A. Decker, Wenting Wu, Jung Sik Kim, Todd Waldman, Robert B. Jenkins, Jann N. Sarkaria

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Deregulation of the p16 INK4a-Cdk4/6-Rb pathway is commonly detected in patients with glioblastoma multiforme (GBM) and is a rational therapeutic target. Here, we characterized the p16 INK4a-Cdk4/6-Rb pathway in the Mayo panel of GBM xenografts, established from primary tissue samples from patients with GBM, and evaluated their response to PD0332991, a specific inhibitor of Cdk4/6. All GBM xenograft lines evaluated in this study had disruptions in the p16 INK4a-Cdk4/6-Rb pathway. In vitro evaluation using short-term explant cultures from selected GBM xenograft lines showed that PD0332991 effectively arrested cell cycle in G1-phase and inhibited cell proliferation dose-dependently in lines deleted for CDKN2A/B-p16 INK4a and either single-copy deletion of CDK4 (GBM22), high-level CDK6 amplification (GBM34), or deletion of CDKN2C/p18 INK4c (GBM43). In contrast, 2 GBM lines with p16 INK4a expression and either CDK4 amplification (GBM5) or RB mutation (GBM28) were completely resistant to PD0332991. Additional xenograft lines were screened, and GBM63 was identified to have p16 INK4a expression and CDK4 amplification. Similar to the Results with GBM5, GBM63 was resistant to PD0332991 treatment. In an orthotopic survival model, treatment of GBM6 xenografts (CDKN2A/B-deleted and CDK4 wild-type) with PD0332991 significantly suppressed tumor cell proliferation and prolonged survival. Collectively, these data support the concept that GBM tumors lacking p16 INK4a expression and with nonamplified CDK4 and wild-type RB status may be more susceptible to Cdk4/6 inhibition using PD0332991.

Original languageEnglish (US)
Pages (from-to)870-881
Number of pages12
JournalNeuro-oncology
Volume14
Issue number7
DOIs
StatePublished - Jul 2012

Keywords

  • Cdk4
  • Cdk6
  • glioblastoma
  • p16
  • retinoblastoma protein

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Cen, L., Carlson, B. L., Schroeder, M. A., Ostrem, J. L., Kitange, G. J., Mladek, A. C., Fink, S. R., Decker, P. A., Wu, W., Kim, J. S., Waldman, T., Jenkins, R. B., & Sarkaria, J. N. (2012). P16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro-oncology, 14(7), 870-881. https://doi.org/10.1093/neuonc/nos114