Pharmacologic Inhibition of Cyclin-Dependent Kinases 4 and 6 Arrests the Growth of Glioblastoma Multiforme Intracranial Xenografts
- 14 April 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (8), 3228-3238
- https://doi.org/10.1158/0008-5472.can-09-4559
Abstract
Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)–proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. Cancer Res; 70(8); 3228–38. ©2010 AACR.Other Versions
This publication has 33 references indexed in Scilit:
- Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastomaBritish Journal of Cancer, 2009
- PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitroBreast Cancer Research, 2009
- Comparative analyses of gene copy number and mRNA expression in glioblastoma multiforme tumors and xenograftsNeuro-Oncology, 2009
- Sample Type Bias in the Analysis of Cancer GenomesCancer Research, 2009
- Cell cycle, CDKs and cancer: a changing paradigmNature Reviews Cancer, 2009
- Mutational Inactivation of PTPRD in Glioblastoma Multiforme and Malignant MelanomaCancer Research, 2008
- An Integrated Genomic Analysis of Human Glioblastoma MultiformeScience, 2008
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma DevelopmentCancer Cell, 2008
- Molecular Determinants of the Response of Glioblastomas to EGFR Kinase InhibitorsNew England Journal of Medicine, 2005