Abstract 2565: Targeting the p38 MAPK pathway inhibits drug resistance in colon adenocarcinoma cells

Abstract

Abstract Despite the recent advances achieved in the treatment of colon cancer, tumour resistance is a frequent cause of chemotherapy failure. Our work was aimed to determine the molecular mechanisms involved in the resistance to irinotecan (SN38), an anticancer agent widely used in colorectal cancer treatment. To this end, we have established an SN38-resistant cellular model from the colon adenocarcinoma cell line HCT-116 and we have obtained 5 resistant clones. In all these five clones we have observed an activation of the MAPK p38 compared to the sensitive cell line called HCT116-s. We have shown in the HCT116-SN6 clone that the p38 pathway is responsible for the resistance to SN38. The family of MAPK p38 counting four isoformes α, β, γ and δ, we have generated cells lines overexpressing each isoforms or inhibiting each isoform expression, and we have demonstrate that the α and β forms are involved in SN38 resistance. In a xenograft model we have shown that the HCT116-SN6 cell line is also resistant to Campto treatment in vivo, and that the α and β isoforms are still responsible for drug resistance. Finally, we have also detected phosphorylated p38 in colon cancer cells of patients resistant to Irinotecan-based chemotherapy. These results show for the first time that the p38 pathway is implicated in the drug sensitivity of colon cancer cells and that targeting p38 could be a good alternative to decrease drug resistance. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2565.