Abstract 2608: Dissecting Myc inhibition as a cancer therapy

Abstract

Abstract The MYC family of basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors are critical for cell growth, proliferation and apoptosis. c-Myc is deregulated in most, if not all, cancers making it an attractive target for cancer therapy. Previously we have shown that Myc inhibition by a mutant c-Myc derivative, Omomyc, leads to tumor regression in several cancer models, notably in murine KRasG12D-driven lung adenocarcinomas. The mechanism by which Omomyc expression leads to tumor regression has not been fully elucidated, nor do we know the biochemical properties of a small molecule that could replicate Omomyc's activity. Therefore, we designed two novel Omomyc mutants (ΔMyc and MMO) that are hypothesised not to interact with the full Omomyc interactome but are still able to inhibit Myc transactivation. We subsequently created human lung adenocarcinoma cell lines (A549s) and transgenic mice which inducibly express Omomyc, ΔMyc and MMO. Unexpectedly Omomyc and ΔMyc inhibited proliferation in vitro but not MMO. In vivo, expression of the mutants has been detected and we are currently assessing their effect on KRasG12D-driven adenocarcinomas. Citation Format: Nicholas J. H. Salisbury, Catherine H. Wilson, Dan Lu, Trevor D. Littlewood, Gerard I. Evan. Dissecting Myc inhibition as a cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2608. doi:10.1158/1538-7445.AM2014-2608