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Abstract
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. 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. 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. 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.
Highlights
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (TKR) playing a key role in the development and progression of several human epithelial cancers
We have previously contributed to clarify some of these mechanisms showing that a Toll-like receptor 9 (TLR9) agonist, immunomodulatory oligonucleotide (IMO), potentiates the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of anti-EGFR monoclonal antibodies (mAb) cetuximab [18] and anti-HER2 mAb trastuzumab [19] in in vivo models of colorectal and breast cancers, respectively. In addition to this immunomodulating function, we showed that IMO acts by impairing EGFR signaling and potently synergizes in vivo both with cetuximab or EGFR tyrosine kinase inhibitors (TKI) gefitinib in EGFR-addicted colorectal cancer models [20]
Because K-Ras mutations are a major limitation for using EGFR inhibitors in patients with colorectal and pancreatic cancer, we investigated the effects of IMO alone and in combination with cetuximab in colon and pancreatic cancer models harboring a mutant K-Ras
Summary
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (TKR) playing a key role in the development and progression of several human epithelial cancers. An emerging issue in cancer patients is the occurrence of constitutive resistance or the development of acquired refractoriness to anti-EGFR drugs by several different mechanisms [6] These include specific mutations or loss of EGFR, alternative signaling by different TKRs, constitutive activation of downstream signal transducers, such as the serine/threonine kinase Akt or the small GTPase Ras, and induction of angiogenesis by tumorderived factors such as the VEGF [1, 7]. Mutations of the K-Ras gene, most frequently in codon 12 of exon 2, produce a single amino acid change resulting in mutant Ras proteins that are insensitive to the function of GTPase— activating protein and are constitutively active These mutations are among the most common genetic alterations in human cancers, occurring in 30% of colorectal cancers, 75% to 90% of pancreatic cancers, 50% of cholangiocarcinomas, and 20% of lung carcinomas [1, 8, 9]. K-Ras mutations leading to constitutive activation of the Ras/MAPK signaling www.aacrjournals.org
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