NDLI: Pharmacologic inhibition of cdk4/6 arrests the growth of glioblastoma multiforme intracranial xenografts

Content Provider	PubMed Central
Author	Michaud, Karine Solomon, David A. Oermann, Eric Kim, Jung-sik Zhong, Wei-zhu Prados, Michael D. Ozawa, Tomoko James, C. David Waldman, Todd
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 Rb-proficient cell lines regardless of other genetic lesions, whereas each of 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. shRNA 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 had significant disease progression or died 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.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-4559
Ending Page	3238
Page Count	11
Starting Page	3228
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	8
Volume Number	70
Language	English
Publisher Date	2010-04-15
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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