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.
OBJECTIVE
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.


METHODS
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 x 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-1 alpha, 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.
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom.
Aoife M
AM
Shannon
Brian A
BA
Telfer
Paul D
PD
Smith
Muhammed
M
Babur
Armelle
A
Logie
Robert W
RW
Wilkinson
Camille
C
Debray
Ian J
IJ
Stratford
Kaye J
KJ
Williams
Stephen R
SR
Wedge
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000532:radiotherapy*; D004341:Drug Evaluation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000532:radiotherapy*; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D029122:Murine pneumonia virus; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2