Data from Anti-DLL4 Inhibits Growth and Reduces Tumor-Initiating Cell Frequency in Colorectal Tumors with Oncogenic <i>KRAS</i> Mutations

Abstract

<div>Abstract<p><i>KRAS</i> mutations are frequent in colorectal cancer (CRC) and are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)–targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway and mediates stem cell self-renewal and vascular development. DLL4 inhibition in colon tumor cells reduces tumor growth and stem cell frequency. Considering the need for new drugs to treat colon cancers with oncogenic <i>KRAS</i> mutations, we examined in this study the efficacy of anti-DLL4 antibodies in <i>KRAS</i> mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant <i>KRAS</i> colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas <i>KRAS</i> wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant <i>KRAS</i> colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant <i>KRAS</i> tumors indicated that the anti-DLL4/irinotecan combination produced a significant decrease in colon cancer stem cell frequency while promoting apoptosis in tumor cells. Our findings provide a rationale for targeting DLL4-Notch signaling for improved treatment of CRC patients with activating <i>KRAS</i> mutations. <i>Cancer Res; 71(5); 1520–5. ©2010 AACR</i>.</p></div>