Abstract 2334: A novel αV integrin antibody, intetumumab (CNTO 95), enhances anti-tumor activity against human non-small cell lung cancer through disruption of the FAK/ERK/AKT pathway and regulation of p27KIP1
Authors: Heidrich Bradley J. , Chen Qiming , Macedo Luciana , Ferrante Catherine A. , Wiley Diana , McCabe Francis L. , Doshi Parul , Marshall Deborah J. 
Published: February 2011

Integrins are cell-surface adhesion proteins that interact with various components of the extracellular matrix and play an important role in intracellular signaling, cell adhesion, migration, and proliferation. The expression of αV integrins has been associated with poor clinical outcome in patients with non-small cell lung cancer (NSCLC).

Intetumumab (CNTO 95) is a novel, fully human monoclonal antibody against all members of the αV integrin family including αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8. Intetumumab inhibits cell adhesion, migration, proliferation, and induces apoptosis in tumor and endothelial cells in vitro. Intetumumab inhibits tumor growth, metastasis, and angiogenesis in vivo in rat xenograft models.

Here, we describe experiments to understand the mechanism of action of intetumumab in NSCLC models in vitro and in vivo. The focal adhesion complex and αV integrins play crucial roles in adhesion, motility, and migration in both normal and cancer cells. NSCLC cells were cultured on a vitronectin matrix to stimulate signaling through the αV integrin pathway and then treated with intetumumab (10 µg/ml). Intetumumab treatment resulted in the reduction of phosphorylated FAK (Y397) and Paxillin (Y31) compared to controls up through 48 hours. FAK has been shown to participate in downstream processes such as cell cycle progression by modulating ERK1/2, AKT and the cyclin-dependent kinase inhibitor p27KIP1. Intetumumab treatment of NSCLC cell lines in vitro resulted in the reduction of phosphorylated ERK1/2 and AKT and the subsequent upregulation of p27KIP1. Furthermore, intetumumab treatment activated the intrinsic pathway of apoptosis as evidenced by the cleavage of caspase 9 and PARP as well as increased Bim expression.

In vivo administration of intetumumab (10 mg/kg, i.p., 3x weekly) alone or in combination with docetaxel (up to 20 mg/kg, i.p., weekly for 3 weeks) significantly inhibited the growth of established A549 human NSCLC tumor xenografts in nude rats as a monotherapy (p&lt;0.030) or in combination with docetaxel (p&lt;0.039). Moreover, in three separate experiments, combination treatment resulted in complete tumor regressions in 76% (25/33) of animals showing superior efficacy of the combination versus either agent alone (p=0.0138).

In conclusion, the results presented here demonstrate the impact of intetumumab on the cellular and molecular mechanisms mediating cell survival through the αV integrin signaling pathway resulting in disruption of focal adhesion complexes, inhibition of cell cycle progression at the G1 phase and induction of the cell intrinsic pathway of apoptosis. Taken together these results demonstrate enhanced anti-tumor efficacy in an established NSCLC preclinical model and suggest the potential for clinical evaluation of intetumumab in NSCLC patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2334.