Abstract 4708: Neuroendocrine gene transcript expression is associated with efficacy to lysine-specific demethylase-1 inhibitor RG6016 in small cell lung cancer-derived cell lines

Abstract

Abstract Small cell lung cancer (SCLC), which comprises 15% of lung neoplasms, is an aggressive malignancy with limited treatment options. Survival in refractory settings is typically less than one year, exemplifying the need for more effective therapeutics. Recent published results suggest that epigenetic modulation mediated by Lysine Specific Demethylase-1 (LSD1) inhibition can impact this disease setting (Mohammed et al., Cell, 2015 28(1):57-69). RG6016 is a potent and selective inhibitor of LSD1 that promotes growth inhibition in vitro and in vivo SCLC xenograft models. Here we describe the identification of a gene expression profile associated with neuroendocrine lineages that predicts responses to RG6016 in SCLC cell lines. RG6016 was screened on a panel of 19 SCLC cell lines; potent sub-nanomolar to nanomolar activity was exhibited on a subset of these cell lines. Growth inhibitory responses were greater in classic compared to variant SCLC cell lines (p-value 0.0055). 9 of the 11 classic SCLC cell lines tested were responsive to growth inhibitory effects of RG6016, while 7 of the 8 variant cell lines were insensitive to RG6016 treatment. Differential gene expression analysis comparing classic to variant cell lines ranked neuroendocrine lineage-associated markers, such as ASCL1, amongst the highest differentially expressed genes (adj. p-value = 2.6 × 10-23). ASCL1 is a transcription factor required for proper development of pulmonary neuroendocrine cells, and was recently identified as essential for the survival of a majority of small cell lung cancers (Augustyn et al., Proc Natl Acad Sci USA 2014 111(41):14788-93). Two other established neuroendocrine markers, DDC and GRP, ranked within the top ten differentially expressed genes. We also found that a subset of insensitive SCLC cell lines harbor c-MYC amplifications, suggesting a potential pathway for resistance to LSD1 inhibition. An RG6016 response gene expression pattern that highly correlates with growth inhibition was defined using baseline expression levels of neuroendocrine lineage transcripts and c-MYC amplification. In vitro activity also correlated with in vivo responses; RG60106 treatment inhibited xenograft growth of response signature positive cell line NCI-H510A, while the response signature negative NCI-H526 xenografts were refractory to RG6016 exposure. Similar gene expression patterns were observed within SCLC cell lines and a panel of SCLC patient samples, suggesting that use of the RG6016 response gene signature may increase the likelihood of identifying patients who will clinically benefit from LSD1- based therapies. Citation Format: Francesca Milletti, Wei-Yi Cheng, Tamara Maes, Serena Lunardi, Mark DeMario, William E. Pierceall, Fiona Mack. Neuroendocrine gene transcript expression is associated with efficacy to lysine-specific demethylase-1 inhibitor RG6016 in small cell lung cancer-derived cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4708.