Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models.

Abstract

PURPOSE:

Results from clinical trials involving resistance to molecularly targeted therapies have revealed the importance of rational single-agent and combination treatment strategies. In this study, we tested the efficacy of a type 1 insulin-like growth factor receptor (IGF1R)/insulin receptor (IR) tyrosine kinase inhibitor, OSI-906, in combination with a mitogen-activated protein (MAP)-ERK kinase (MEK) 1/2 inhibitor based on evidence that the MAP kinase pathway was upregulated in colorectal cancer cell lines that were resistant to OSI-906.

EXPERIMENTAL DESIGN:

The antiproliferative effects of OSI-906 and the MEK 1/2 inhibitor U0126 were analyzed both as single agents and in combination in 13 colorectal cancer cell lines in vitro. Apoptosis, downstream effector proteins, and cell cycle were also assessed. In addition, the efficacy of OSI-906 combined with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) was evaluated in vivo using human colorectal cancer xenograft models.

RESULTS:

The combination of OSI-906 and U0126 resulted in synergistic effects in 11 of 13 colorectal cancer cell lines tested. This synergy was variably associated with apoptosis or cell-cycle arrest in addition to molecular effects on prosurvival pathways. The synergy was also reflected in the in vivo xenograft studies following treatment with the combination of OSI-906 and selumetinib.

CONCLUSIONS:

Results from this study demonstrate synergistic antiproliferative effects in response to the combination of OSI-906 with an MEK 1/2 inhibitor in colorectal cancer cell line models both in vitro and in vivo, which supports the rational combination of OSI-906 with an MEK inhibitor in patients with colorectal cancer. Clin Cancer Res; 19(22); 6219-29. ©2013 AACR.

• Authors: Sara A Flanigan, Todd M Pitts, Timothy P Newton, Gillian N Kulikowski, Aik Choon Tan, Martine C McManus, Anna Spreafico, Maria I Kachaeva, Heather M Selby, John J Tentler, S Gail Eckhardt, Stephen Leong
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 22 Pg. 6219-29 (Nov 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 24045180 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• AZD 6244
• Benzimidazoles
• Butadienes
• Enzyme Inhibitors
• Imidazoles
• Nitriles
• Protein Kinase Inhibitors
• Pyrazines
• U 0126
• Receptor, IGF Type 1
• Receptor, Insulin
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Map2k1 protein, mouse
• Map2k2 protein, mouse
• Caspase 3
• Caspase 7

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzimidazoles (pharmacology)
• Butadienes (pharmacology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Cycle (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Imidazoles (pharmacology)
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Nitriles (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Receptor, Insulin (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Transplantation, Heterologous