ePrints

The mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY- 142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts

Lookup NU author(s): Professor Steve WedgeORCiD

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

Abstract

Purpose: Novel molecularly targeted agents, given in combination with radiotherapy, have the potential to increase tumor response rates and the survival of patients with lung cancer. AZD6244 is a potent and selective inhibitor of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2), a critical enzyme within the MAPK/extracellular signal-regulated kinase (ERK) signaling pathway that regulates the proliferation and survival of tumor cells. Experimental Design: This study examined the potential benefit of combining AZD6244 with fractionated radiotherapy using human lung and colon carcinoma xenograft models. Results: AZD6244 reduced ERK phosphorylation in Calu-6 lung cancer cells in vitro. Administration of AZD6244 for 10 days (25 mg/kg twice daily p.o.) inhibited the tumor growth of Calu-6 xenografts, with regrowth occurring on cessation of drug treatment. When fractionated tumor-localized radiotherapy (5 × 2 Gy) was combined with AZD6244 treatment, the tumor growth delay was enhanced significantly when compared with either modality alone, and this effect was also seen in a colon tumor model. We examined the effect of inhibiting MEK1/2 on the molecular responses to hypoxia, a potential interaction that could contribute to radioresponsiveness. AZD6244 reduced hypoxia-inducible factor–specific transactivation in vivo, shown using Calu-6 dual clone cells that stably express a Firefly luciferase gene under the control of a hypoxia-driven promoter. Furthermore, hypoxia-inducible factor-1α, GLUT-1, and vascular endothelial growth factor levels were reduced by AZD6244, and there was a significant decrease in vascular erfusion in the tumors given combination treatment when compared with the other treatment groups. Conclusions: These data provide support for the clinical development of AZD6244 in combination with radiotherapy and indicate a potential role for AZD6244 in inhibiting the tumor hypoxia response.

Publication metadata

Author(s): Shannon AM, Telfer BA, Smith PD, Babur M, Logie A, Wilkinson RW, Debray C, Stratford IJ, Williams KJ, Wedge SR

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2009

Volume: 15

Issue: 21

Pages: 6619-6629

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-08-2958

DOI: 10.1158/1078-0432.CCR-08-2958

Altmetrics

Share