Data from Overcoming IGF1R/IR Resistance through Inhibition of MEK Signaling in Colorectal Cancer Models

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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 <i>in vitro</i>. 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 <i>in vivo</i> using human colorectal cancer xenograft models.</p><p><b>Results:</b> 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 <i>in vivo</i> xenograft studies following treatment with the combination of OSI-906 and selumetinib.</p><p><b>Conclusions:</b> 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 <i>in vitro</i> and <i>in vivo</i>, which supports the rational combination of OSI-906 with an MEK inhibitor in patients with colorectal cancer. <i>Clin Cancer Res; 19(22); 6219–29. ©2013 AACR</i>.</p></div>