Data from Toll-like Receptor 9 Agonist IMO Cooperates with Cetuximab in <i>K</i>-<i>Ras</i> Mutant Colorectal and Pancreatic Cancers

Abstract

<div>Abstract<p><b>Purpose:</b><i>K-Ras</i> somatic mutations are a strong predictive biomarker for resistance to epidermal growth factor receptor (EGFR) inhibitors in patients with colorectal and pancreatic cancer. We previously showed that the novel Toll-like receptor 9 (TLR9) agonist immunomodulatory oligonucleotide (IMO) has a strong <i>in vivo</i> activity in colorectal cancer models by interfering with EGFR-related signaling and synergizing with the anti-EGFR monoclonal antibody cetuximab.</p><p><b>Experimental Design:</b> In the present study, we investigated, both <i>in vitro</i> and <i>in vivo</i>, the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and orthotopic pancreatic cancer models harboring <i>K-Ras</i> mutations and resistance to EGFR inhibitors.</p><p><b>Results:</b> We showed that IMO was able to significantly restore the sensitivity of <i>K-Ras</i> mutant cancer cells to cetuximab, producing a marked inhibition of cell survival and a complete suppression of mitogen—activated protein kinase phosphorylation, when used in combination with cetuximab. IMO interfered with EGFR-dependent signaling, modulating the functional interaction between TLR9 and EGFR. <i>In vivo</i>, IMO plus cetuximab combination caused a potent and long-lasting cooperative antitumor activity in LS174T colorectal cancer and in orthotopic AsPC1 pancreatic cancer. The capability of IMO to restore cetuximab sensitivity was further confirmed by using <i>K-Ras</i> mutant colorectal cancer cell models obtained through homologous recombination technology.</p><p><b>Conclusions:</b> We showed that IMO markedly inhibits growth of <i>K-Ras</i> mutant colon and pancreatic cancers <i>in vitro</i> and in nude mice and cooperates with cetuximab via multiple mechanisms of action. Therefore, we propose IMO plus cetuximab as a therapeutic strategy for <i>K-Ras</i> wild-type as well for <i>K-Ras</i> mutant, cetuximab-resistant colorectal and pancreatic cancers. <i>Clin Cancer Res; 17(20); 6531–41. ©2011 AACR</i>.</p></div>