title: Toll-like receptor 9 agonist IMO cooperates with cetuximab in K-ras mutant colorectal and pancreatic cancers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  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.
authors: Dipartmento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli Federico II, Naples, Italy.
authors: Roberta
authors: R
authors: Rosa
authors: Davide
authors: D
authors: Melisi
authors: Vincenzo
authors: V
authors: Damiano
authors: Roberto
authors: R
authors: Bianco
authors: Sonia
authors: S
authors: Garofalo
authors: Teresa
authors: T
authors: Gelardi
authors: Sudhir
authors: S
authors: Agrawal
authors: Federica
authors: F
authors: Di Nicolantonio
authors: Aldo
authors: A
authors: Scarpa
authors: Alberto
authors: A
authors: Bardelli
authors: Giampaolo
authors: G
authors: Tortora
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009841:Oligonucleotides / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D011897:Random Allocation; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009841:Oligonucleotides; D051217:Toll-Like Receptor 9; D000068818:Cetuximab