Abstract 603: Adenoviral mediated expression of Omomyc induced growth inhibition and apoptosis in lung cancer expressing Myc

Abstract

Abstract The Myc basic helix-loop-helix zipper domain determines dimerization with the constitutively expressed bHLH-Zip protein, Max, and also binding to the DNA E-box. Both of these functions play a critical role in the Myc regulation of growth, proliferation, tumorigenesis, and apoptosis. It has been reported that Myc recognition specificity is encoded in a short region within the leucine zipper. Mutation of four amino acids (E57T, E64I, R70Q, and R71N) generates a protein, Omomyc, that homodimerizes efficiently and can still heterodimerize with wild type Myc and Max. As a consequence, Omomyc suppresses activation of artificial E-box promoter elements by Myc/Max and strongly potentiates Myc-induced apoptosis in a manner dependent on Myc expression levels. Furthermore, Omomyc prevents initiation of K-RasG12D-induced lung tumors (Soucek L et al. Oncogene. 17: 2463-72. 1998, Nature. 455:679-83. 2008). In this study we have constructed an adenoviral vector (Ad-Omomyc) for use as a novel therapy for Myc or K-Ras mutated cancer. Ad-Omomyc expresses Omomyc and is driven by the CMV promoter. MTS assay and flowcytometric analysis demonstrated that Ad-Omomyc significantly suppressed cell viability and induced apoptosis in A549 pulmonary adenocarcinoma cells, which express Myc and harbor K-Ras mutations. Moreover, the combination treatment of Ad-Myc and Ad-Omomyc increased apoptosis in H441 pulmonary adenocarcinoma cells harboring a K-Ras mutation as compared to administering Ad-Omomyc alone. Ad-Omomyc induced little apoptosis in normal human lung fibroblasts (NHLF). Here, we describe a novel strategy to target Myc or K-Ras for the treatment of lung cancer using a Myc derivative: Omomyc. 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 603.