Abstract A22: Differential MYC dependence in NSCLC identified through pharmacological and genetic MYC inhibition

Abstract

Abstract MYC is one of the most commonly deregulated oncogenes in various cancers, including breast, colorectal and lung. While mutations are rare, we know that MYC is overexpressed and in some cases amplified in these (and other) cancers. Numerous reports have recently demonstrated the utility of various therapeutics in selectively targeting MYC-driven cancers. However, given the lack of consistency across tissue types, particularly lung cancer, a multimodal approach to delineate MYC-dependent lung cancers is required. Our goal is to identify lung cancers that are addicted to MYC, determine their oncogenotype and molecular properties, and identify a biomarker to identify patients with MYC addicted tumors. We studied a large panel of clinically and molecularly annotated NSCLC lines for MYC mRNA, protein expression, and DNA copy number. Functional tests were performed on 17 NSCLC cell lines using three drugs that were recently shown to selectively target MYC-driven cancers. Further, we utilized the dominant negative mini-protein OMOMYC for functional classification. In all cases, effects were monitored by colony forming efficiency (CFE) assays and proliferation assays. OMOMYC results were confirmed via xenograft experiments. Each of the three MYC inhibitors tested elicited a viability response in a subset of the 17 NSCLC cell lines, though the sensitive subset was not significantly similar between any two drugs (highest correlation coefficient of 0.3). In order to determine which, if any, of the drugs truly targeted MYC-driven lung cancers, we stably expressed OMOMYC in all 17 parental NSCLC cells and performed functional assays. 6/17 cell lines were dramatically sensitive to OMOMYC (with up to 100 fold reduction in CFE), compared to 11/17 totally resistant. The viability in the presence of OMOMYC shows a statistically significant correlation with one of the three MYC inhibitors tested, which supports the notion that this sensitive subset represents a truly MYC-dependent class of lung cancers. Surprisingly, there was no correlation between MYC dependence and either MYC mRNA, protein expression or DNA copy number. OMOMYC levels were normalized in all cell lines tested and quantified using qRT-PCR. Additionally, in all cases, exogenous OMOMYC expression led to down regulation of c-Myc target genes as measured by both qRT-PCR and microarray. These data suggest that the observed phenotype was the result of decreased MYC activity. We conclude: there is a subset of NSCLCs that demonstrates dramatic growth inhibition by a single MYC-inhibitor, and these data are phenocopied by the more specific MYC-dominant negative protein, OMOMYC. We are classifying this subset of cancer cell lines, MYC “addicted.” Using the MYC “addicted” vs. non- addicted NSCLC panel, we are testing for gene expression, methylation and mutational differences in order to identify and eventually characterize a biomarker for MYC dependence in lung cancer. Citation Format: Patrick Dospoy, Chunli Shao, Elizabeth McMillan, Michael Peyton, Jill Larsen, Luc Girard, Ignacio Wistuba, Adi F. Gazdar, John D. Minna. Differential MYC dependence in NSCLC identified through pharmacological and genetic MYC inhibition. [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 A22.