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

• Published in: Clinical cancer research Vol. 15; no. 21; pp. 6619 - 6629
• Main Authors: Shannon, Aoife M., Telfer, Brian A., Smith, Paul D., Babur, Muhammed, Logie, Armelle, Wilkinson, Robert W., Debray, Camille, Stratford, Ian J., Williams, Kaye J., Wedge, Stephen R.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.11.2009
• Subjects: Animals; Benzimidazoles - pharmacology; Cell Hypoxia - drug effects; Cell Line, Tumor; Colorectal Neoplasms - radiotherapy; Drug Evaluation; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Humans; hypoxia; Lung Neoplasms - radiotherapy; MAP Kinase Kinase 1; MAP Kinase Kinase 2 - antagonists & inhibitors; MEK inhibitor; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Murine pneumonia virus; Protein Kinase Inhibitors - pharmacology; Radiation-Sensitizing Agents - pharmacology; radiotherapy; VEGF; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-2958

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 perfusion 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. (Clin Cancer Res 2009;15(21):6619–29)