477 Jab1/Csn5: a new player driving the resistance to HER2-targeted therapies for breast cancer

Abstract

JNK1 and JNK2, respectively) to assess the role of JNK and its iso-forms in hypoxic resistance of colon cancer cell lines to oxaliplatin. Combination indices for oxaliplatin and CC-401 were calculated based on MTT assays. Induction of cell death and DNA damage were studied using flow cytometry. Studies involving stable introduction of dominant negative JNK1 or JNK2 were conducted both on monoclonal cell lines (HT29-derived) and pooled cells (SW620, HCT116). Results: Our data demonstrate that stress signaling through JNK is induced by hypoxia in the majority of colon cancer cell lines assessed. Hypoxic resistance to oxaliplatin varies significantly, implying cell-specific effects of JNK on sensitivity. Pharmacological inhibition of JNK augments the cytotoxicity of oxaliplatin in multiple colon cancer cell lines. We also show that colon cancer cell lines differ in their responses to oxaliplatin when JNK1 or JNK2 are down-regulated, from no effect (HCT116) to increased sensitivity (HT29, SW620). Neither pharmacological, nor molecular inhibition of JNK affects significantly hypoxiaor oxaliplatininduced DNA damage. In hypoxic HT29 cells, CC-401 shows synergism with oxaliplatin, SN-38 and 5-FU with CI50 of 0.42, 0.6 and 0.63, respectively. Finally, we confirm enhancement of oxaliplatin efficacy by CC401 in vivo, in HT29-derived mouse xenografts. Conclusions: These findings in vitro and in vivo support the involvement of JNK1 in resistance to cytotoxic therapy in colorectal cancer models. Inhibition of this pathway may be a rational therapeutic approach.