Abstract 4097: Sorafenib sensitizes solid tumors to TRAIL or TRAIL receptor agonist antibodies

Abstract

Abstract Solid carcinomas display considerable resistance to chemotherapeutic drugs and tumor cell apoptosis-inducing agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. A phase III clinical trial with the multi-kinase inhibitor sorafenib (Nexavar) in Hepatoceullular carcinoma (HCC) was completed leading to the first FDA-approved drug therapy for liver cancer in 2007. Phase I/II trials have been completed with a fully-human anti-TRAIL death receptor 1 (DR4) agonist antibody (mapatumumab) in non small-cell lung carcinoma and non-Hodgkin's lymphoma and phase I trials with an anti-TRAIL-R2 (DR5) monoclonal antibody (lexatumumab) in advanced cancers. We hypothesized that sorafenib and TRAIL or sorafenib and TRAIL receptor agonist antibodies (mapatumumab or lexatumumab) may overcome resistance to apoptosis in a panel of TRAIL-resistant solid carcinoma cell lines. We observed that sorafenib induces apoptosis of HepG2 and Hep3B cells in a dose-dependent manner. In addition, sorafenib is a potent sensitizer of HCC cell lines to TRAIL. We have also found that single agent lexatumumab causes cell death in HepG2, Hep3B and SNU449 cells whereas mapatumumab does not. The combination of sorafenib with TRAIL or either TRAIL receptor agonist antibody enhances apoptosis in HCC cell lines. We found that in other solid tumor types including prostate, breast and colon cancer there is a synergistic interaction between sorafenib and TRAIL or TRAIL receptor agonist antibodies. Furthermore, these combinations prevent the growth of tumors in vivo. Sorafenib downregulates the expression of Mcl-1 protein, a member of the Bcl-2 family that has been previously found to be overexpressed in about 50% of HCC patient samples. Sorafenib was also found to inhibit Stat3 activation by Jak2 kinases. These findings suggest a molecular rationale for combining these agents in therapy of solid tumors in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4097. doi:10.1158/1538-7445.AM2011-4097