Abstract IA12: Mechanisms of MYC addiction

Abstract

Abstract Many human cancers are caused by the activation of the MYC oncogene. We have developed experimental transgenic mouse models to model and predict the therapeutic efficacy of targeted therapy of oncogenes. Using the Tet system, we can conditionally regulate oncogene expression in vivo in a temporally controlled and tissue specific manner. We have shown that many oncogenes (MYC, RAS, BCR-ABL) induce tumorigenesis that is completely reversible upon their inactivation. We have described this phenomenon as oncogene addiction. Oncogene addiction is associated with proliferative arrest, apoptosis, differentiation, cellular senescence and the shutdown of angiogenesis. The specific consequences of MYC oncogene inactivation depend both on the genetic and cellular context. In some cases, even brief inactivation of an oncogene can result in sustained tumor regression. In other cases, oncogene inactivation is associated with tumor dormancy. Tumor cell intrinsic and host-dependent cell autonomous mechanisms are involved. Tumor cell intrinsic mechanisms appear to involve mechanisms that are dependent upon DNA repair processes, the regulation of protein synthesis and of cellular metabolism. Host-dependent mechanisms include the regulation of angiogenesis and immune cell elimination. In addition, tumor cells secrete autocrine factors critical to oncogene addiction. We have uncovered that oncogene addiction is both dependent upon cell autonomous and host cell dependent mechanisms. Thus, MYC via miR17-92 regulates chromatin regulatory gene products required to in a cell autonomous manner regulate cellular proliferation, survival and self-renewal programs. However, MYC through regulation of host immune mechanisms and the recruitement of CD4+ T-cells, in a host cell dependent manner, regulates the tumor microenvironment. Our experimental model systems have been employed to generate nanotechnologies and molecular imaging approaches as well as innovative therapies to respectively predict and to elicit MYC addiction. Citation Format: Dean Felsher. Mechanisms of MYC addiction. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA12.