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Research Articles: Therapeutics, Targets, and Development

Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo

¹ Brain Tumor Center, Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center; ² Graduate School of Biomedical Sciences, The University of Texas-Houston Health Science Center, Houston, Texas; ³ Lab. Head of Discovery Biology, Novartis Institutes for BioMedical Research, Tsukuba, Ibaraki, Japan; ⁴ Expertise Program Kinases, Novartis Institutes for BioMedical Research, Basel, Switzerland; and ⁵ MedImmune, Inc., Gaithersburg, Maryland

Requests for reprints: Ta-Jen Liu, Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 1002, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-834-6203; Fax: 713-834-6230. E-mail: tjliu{at}mdanderson.org

Abstract

Multiple genetic aberrations in human gliomas contribute to their highly infiltrative and rapid growth characteristics. Focal adhesion kinase (FAK) regulates tumor migration and invasion. Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with tumor grade, is involved in proliferation and survival. We hypothesized that inhibiting the phosphorylation of FAK and IGF-IR by NVP-TAE226 (hereafter called TAE226), a novel dual tyrosine kinase inhibitor of FAK and IGF-IR, would suppress the growth and invasion of glioma cells. In culture, TAE226 inhibited extracellular matrix–induced autophosphorylation of FAK (Tyr³⁹⁷). TAE226 also inhibited IGF-I–induced phosphorylation of IGF-IR and activity of its downstream target genes such as MAPK and Akt. TAE226 retarded tumor cell growth as assessed by a cell viability assay and attenuated G₂-M cell cycle progression associated with a decrease in cyclin B1 and phosphorylated cdc2 (Tyr¹⁵) protein expression. TAE226 treatment inhibited tumor cell invasion by at least 50% compared with the control in an in vitro Matrigel invasion assay. Interestingly, TAE226 treatment of tumor cells containing wild-type p53 mainly exhibited G₂-M arrest, whereas tumor cells bearing mutant p53 underwent apoptosis. Induction of apoptosis by TAE226 was substantiated by detection of caspase-3/7 activation and poly(ADP-ribose) polymerase cleavage and by an Annexin V apoptosis assay. More importantly, TAE226 treatment significantly increased the survival rate of animals in an intracranial glioma xenograft model. Collectively, these data show that blocking the signaling pathways of FAK and IGF-IR with TAE226 has the potential to be an efficacious treatment for human gliomas. [Mol Cancer Ther 2007;6(4):1357–67]

Grant support: Commonwealth Cancer Foundation and M. D. Anderson Cancer Center Support grant CA16672.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 8/06; revised 12/ 7/06; accepted 2/26/07.

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