title: Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations.
abstract: KRAS 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 KRAS mutations, we examined in this study the efficacy of anti-DLL4 antibodies in KRAS mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant KRAS colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas KRAS wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant KRAS colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant KRAS 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 KRAS mutations.
authors.affiliation: OncoMed Pharmaceuticals, Inc., Redwood City, California 94063, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.forename: Wan-Ching
authors.initials: WC
authors.lastname: Yen
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Gilbert
authors.initials: G
authors.lastname: O'Young
authors.forename: John
authors.initials: J
authors.lastname: Lewicki
authors.forename: Austin
authors.initials: A
authors.lastname: Gurney
authors.forename: Timothy
authors.initials: T
authors.lastname: Hoey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002135:Calcium-Binding Proteins; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002469:Cell Separation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D000077146:Irinotecan; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002166:Camptothecin