Abstract 3578: Comprehensive pharmacogenomic analysis establishes lncRNAs as protein-coding independent biomarker of drug response in human cancers

Abstract

Abstract Somatic alterations in the cancer genome influence a patient’s response to anti-cancer therapeutics. Thus, identifying context-specific alterations associated with differential drug sensitivity can improve patient response prediction and therapeutic selection. The discovery of pervasive dysregulation of long non-coding RNAs (lncRNA) in human cancers and their perceived role in gene regulation has led to the speculation that lncRNAs may also play a role in determining cancer drug response. However, it is unclear whether lncRNAs can augment the existing, predominantly protein coding, repertoire of pharmacogenomic biomarkers of anti-cancer agents. We performed comprehensive analysis of whole genome and transcriptome data from over 1000 cancer cell lines and drug screening data for over 500 anti-cancer agents to systematically analyze over 5 million lncRNA-drug associations. We developed statistical and machine-learning frameworks to study these associations while controlling for the effects of confounding PCGs. Sparse regression and network-based methods demonstrated the predictive ability and biological relevance of literature-supported and novel lncRNAs biomarkers. Using regression analysis of lncRNA expression controlling for neighboring PCGs against drug response, we established that a large proportion of the lncRNAs candidates are PCG-independent biomarkers and potent predictors of cancer drug response. We further identified response-associated somatic alterations specifically in lncRNA genome that do not overlap PCGs. In addition, we demonstrated that collinear lncRNAs might be biologically relevant determinants of drug response. As an example, we identified EGFR-AS1 and MIR205HG as novel predictors of anti-EGFR therapy, which explain a significantly larger proportion of variability in erlotinib and gefitinib response as compared to EGFR mutations and copy-number alterations in drug screens and in patient data. We validated our findings in 16 non-small cell lung cancer and erlotinib-resistant cell lines. Our knockdown experiments revealed mechanisms of erlotinib sensitivity mediated by the two lncRNAs without influencing EGFR expression. In conclusion, our comprehensive analysis generated unprecedented insights into the role of lncRNAs in cancer drug response that reaches beyond PCGs. This study will serve as a foundation for future cancer pharmacogenomic studies and will be an invaluable resource for investigators seeking insights into mechanisms of drug response. Citation Format: Aritro Nath, Eunice Y. Lau, Adam M. Lee, Paul Geeleher, William C. Cho, R. Stephanie Huang. Comprehensive pharmacogenomic analysis establishes lncRNAs as protein-coding independent biomarker of drug response in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3578.