AWARD NUMBER: W81XWH-07-1-0268 TITLE: Modulators of Response to Tumor Necrosis-related Apoptosis Inducing Ligand (TRAIL) Therapy in Ovarian Cancer PRINCIPAL INVESTIGATOR:

Background: Signaling by Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) and Fas ligand (FasL) has been proposed to contribute to the chemosensitivity of tumor cells treated with various other anti-cancer agents. However, the importance of these effects and whether there are differences in vitro and in vivo is unclear. Methodology/Principal Findings: To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells, we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1. Inhibition of TRAIL receptors did not affect in vitro tumor cell killing by various anti-cancer agents indicating that chemosensitivity is not significantly affected by the tumor cell-intrinsic activation of death receptor signaling. However, selective inhibition of TRAIL receptor signaling caused reduced tumor regression and clearance in vivo when tested in a NOD/SCID mouse model. Conclusions: These data show that TRAIL receptor signaling in tumor cells can determine chemosensitivity in vivo but not in vitro and thus imply that TRAIL resistance makes tumors less susceptible to conventional cytotoxic anti-cancer drugs as well as drugs that directly target the TRAIL receptors. Citation: Menke C, Goncharov T, Qamar L, Korch C, Ford HL, et al. (2011) TRAIL Receptor Signaling Regulation of Chemosensitivity In Vivo but Not In Vitro. PLoS ONE 6(1): e14527. doi:10.1371/journal.pone.0014527 Editor: Eric J. Bernhard, National Cancer Institute, United States of America Received July 26, 2010; Accepted December 10, 2010; Published January 14, 2011 Copyright: 2011 Menke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by National Institutes of Health (NIH) grants RO1CA 111421 (A.T.), RO1CA 124545 (A.T., H.F. & K.B.) and Department of Defense OC060143 (K.B.) and core facilities supported by the NIH-National Cancer Institute Support Grant (P30 CA46934) to University of Colorado Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] ¤ Current address: Department of Protein Engineering, Genentech, Inc., South San Francisco, California, United States of America