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.
Highlights
Epidermal growth factor receptor (EGFR), a member of the HER-ErbB family of receptor tyrosine kinases, plays an important role in modulating cellular proliferation, adhesion, angiogenesis, migration, and survival in colorectal cancer (CRC; ref. 1)
We identified another mechanism of action of anti-Delta-like 4 ligand (DLL4) directly acting on tumor cells and reducing cancer stem cell frequency in colon and breast tumors [15]
We evaluated the effect of anti-epidermal growth factor receptor (EGFR) antibody cetuximab on the growth of KRASWT and KRASMT colorectal xenograft tumors
Summary
Epidermal growth factor receptor (EGFR), a member of the HER-ErbB family of receptor tyrosine kinases, plays an important role in modulating cellular proliferation, adhesion, angiogenesis, migration, and survival in colorectal cancer (CRC; ref. 1). Epidermal growth factor receptor (EGFR), a member of the HER-ErbB family of receptor tyrosine kinases, plays an important role in modulating cellular proliferation, adhesion, angiogenesis, migration, and survival in colorectal cancer Treatment resistance to EGFR-targeted monoclonal antibodies cetuximab or panitumumab [6,7,8,9] These clinical findings have led the European Medical Agency (EMEA) to restrict the use of anti-EGFR antibodies to CRC patients with wild-type KRAS. Based on a comprehensive review of the relevant literature, the American Society of Clinical Oncology released a Provisional Clinical Opinion recommending that metastatic CRC patients with a KRAS mutation in codons 12 or 13 should not receive anti-EGFR antibody therapy [10]. There is a critical need for new therapies to treat the large segment of CRC patients with activating KRAS mutations. Anti-DLL4 Is Active in KRAS Mutant Tumors antitumor effect of anti-DLL4 on colorectal tumors bearing oncogenic KRAS mutations using colorectal human tumor xenograft models derived from patient samples
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