Toll-Like Receptor 9 Agonist IMO Cooperates with Cetuximab in K-Ras Mutant Colorectal and Pancreatic Cancers
Menée in vitro et in vivo, cette étude évalue les effets d'un composé appelé IMO, un agoniste de TLR9, dans les cancers du côlon-rectum et du pancréas résistant au cetuximab et présentant des mutations du gène K-Ras
Purpose. K-Ras somatic mutations is a strong predictive biomarker for resistance to EGFR inhibitors in colorectal and pancreatic cancer patients. We previously demonstrated that the novel Toll-like Receptor 9 (TLR9) agonist IMO has a strong in vivo activity in colorectal cancer models by interfering with Epidermal Growth Factor Receptor (EGFR)-related signalling and synergizing with the anti-EGFR monoclonal antibody cetuximab. 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 harbouring K-Ras mutations and resistant to EGFR inhibitors. Results. 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 MAPK phosphorylation, when used in combination with cetuximab. IMO interfered with EGFR-dependent signalling 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. IMO capability to restore cetuximab sensitivity was further confirmed by using K-Ras mutant colorectal cancer cell models obtained through homologous recombination technology. Conclusions. We demonstrated 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.