Improving Pancreatic Cancer Drug Discovery By Leveraging Genomics To Select Better In Vitro Models

Currently, pancreatic cancer has an estimated 5-year survival rate of only 5-6%. The projection that pancreatic cancer will be the second leading cause of cancer related death by 2020 compounded by the numerous clinical trial failures precipitates the need for novel approaches to accelerate progress in new medicine development. Cell lines used for screening pre-clinical compounds prior to animal models and human testing are usually chosen based on ease of access and literature prevalence. However, the constellation of genomic derangements in cell lines commonly used for in vitro studies may not be representative of pancreatic cancer. In this study, we leveraged copy number variation (CNV) and targeted sequencing data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) to predict optimal cell lines that mirror pancreatic cancer genomes most closely. We calculated the frequency of each CCLE pancreatic cancer cell line in literature and compared this to how well each cell line recapitulates the pancreatic cancer population. Unsurprisingly, we observed that CCLE pancreatic cancer cell lines overall have more frequent CNVs and mutations than TCGA pancreatic cancer tumors. This observation is likely due to inherent genomic instability of cell lines and underscores the importance of using low passage cells. Next, we directly compared the median per gene CNV values in TCGA pancreatic cancer tumors and pancreatic cancer cell lines in CCLE. Contrary to our expectation, the top five cell lines by CNV correlation with TCGA pancreatic tumors represented only 6% out of all literature search hits for all CCLE pancreatic cancer cell lines, indicating the availability of more optimal cell lines from a genomics perspective. Additionally, we leveraged targeted sequencing data to compare the most frequent mutations with medium to high Mutation Assessor scores in TCGA pancreatic cancer tumors to CCLE pancreatic cancer cell lines. The seven most common mutations by this method in TCGA pancreatic cancer tumors were: KRAS, TP53, MYH8, TAOK2, PCDH15, ATRX, and CDKN2A. Using hierarchical clustering based on the presence or absence of these 7 mutations in pancreatic cancer CCLE cell lines and TCGA tumors, we showed that some cell lines readily clustered amongst TCGA tumors (such as BXPC3), while others occupied discrete branches of the dendrogram exclusive of most TCGA tumors such as PK1 and PANC1. This implies that while some cell line mimic pancreatic tumor mutations closely, others represent mutation constellations not commonly observed in patients. It is possible to apply this method to other cancer types, given consideration for potentially different cancer biology. In summary, our work reports that many popular pancreatic cancer cell lines harbor distinct genomic aberration profiles from pancreatic cancer tumors and highlights the emerging role of genomics in advancing the clinical success of therapeutic trials. Citation Format: Yoonjeong Cha, Andrew Lysaght, Rain Cui, Brian Weiner, Sarah Kolitz, Fadi Towfic, Jason Funt, Kevin Fowler, Badri Vardarajan, Maxim Artyomov, Benjamin Zeskind, Rebecca Kusko. Improving pancreatic cancer drug discovery by leveraging genomics to select better in vitro models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4741. doi:10.1158/1538-7445.AM2015-4741