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Toll-like receptor 9 agonist IMO cooperates with cetuximab in K-ras mutant colorectal and pancreatic cancers.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2011 Oct 15; Vol. 17 (20), pp. 6531-41. Date of Electronic Publication: 2011 Sep 02. - Publication Year :
- 2011
-
Abstract
- Purpose: K-Ras 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 in vivo activity in colorectal cancer models by interfering with EGFR-related signaling and synergizing with the anti-EGFR monoclonal antibody cetuximab.<br />Experimental Design: In the present study, we investigated, both in vitro and in vivo, the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and orthotopic pancreatic cancer models harboring K-Ras mutations and resistance to EGFR inhibitors.<br />Results: We showed that IMO was able to significantly restore the sensitivity of K-Ras 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. In vivo, 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 K-Ras mutant colorectal cancer cell models obtained through homologous recombination technology.<br />Conclusions: We showed that IMO markedly inhibits growth of K-Ras mutant colon and pancreatic cancers in vitro and in nude mice and cooperates with cetuximab via multiple mechanisms of action. Therefore, we propose IMO plus cetuximab as a therapeutic strategy for K-Ras wild-type as well for K-Ras mutant, cetuximab-resistant colorectal and pancreatic cancers.<br /> (©2011 AACR.)
- Subjects :
- Animals
Antibodies, Monoclonal, Humanized
Cell Line, Tumor
Cetuximab
Colorectal Neoplasms drug therapy
Colorectal Neoplasms genetics
Drug Resistance, Neoplasm drug effects
Humans
Mice
Mice, Nude
Mutation
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms genetics
Random Allocation
Xenograft Model Antitumor Assays
Antibodies, Monoclonal administration & dosage
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Genes, ras
Oligonucleotides therapeutic use
Toll-Like Receptor 9 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 17
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 21890455
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-10-3376