Abstract 214: Genetic and transcriptional instability alters cell line drug response

Inconsistencies in cell line-based studies jeopardize reproducibility of cancer research. Natural evolution leading to genetic and transcriptional heterogeneity within cancer cell lines may contribute to such inconsistencies. To systematically test this hypothesis, we performed comprehensive genetic and transcriptomic characterization of 27 strains of the common breast cancer cell line MCF7, and then assessed the response of those strains to 321 anti-cancer compounds. We found extensive variation in genomic profiles and responses to small molecules across strains. Genetic variation occurred at all levels – point mutations, rearrangements, and copy number changes – and affected multiple oncogenes and tumor suppressor genes. Similar findings were obtained across 23 strains of the lung cancer cell line A549, indicating that such variation is a general property of cancer cell lines. These changes resulted in substantial differences in gene expression programs, cell morphology and proliferation, and strikingly high variability in drug response. Over 75% of the compounds that exhibited strong activity in some of the strains, were completely inactive in other strains. These results indicate that genomic variation within commonly used cancer cell lines is extensive, resulting in disparate drug responses. Such variation may contribute to difficulties in conducting reproducible cell line-based studies. Citation Format: Uri Ben-David, Ben Siranosian, Gavin Ha, Helen Tang, Nicholas J. Lyons, Robert Burns, Anwesha Nag, Beth Cimini, Peter Tsvetkov, Andrew A. Tubelli, Bang Wong, Aaron R. Thorner, Joshua Bittker, Matthew Meyerson, Rameen Beroukhim, Todd R. Golub. Genetic and transcriptional instability alters cell line drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 214.