More than fishing for a cure: The promises and pitfalls of high throughput cancer cell line screens

Abstract

High-throughput screens in cancer cell lines (CCLs) have been used for decades to help researchers identify compounds with the potential to improve the treatment of cancer and, more recently, to identify genomic susceptibilities in cancer via genome-wide shRNA and CRISPR/Cas9 screens. Additionally, rich genomic and transcriptomic data of these CCLs has allowed researchers to pair this screening data with biological features, enabling efforts to identify biomarkers of treatment response and gene dependencies. In this paper, we review the major CCL screening efforts and the large datasets these screens have made available. We also assess the CCL screens collectively and include a resource with harmonized CCL and compound identifiers to facilitate comparisons across screens. The CCLs in these screens were found to represent a wide range of cancer types, with a strong correlation between the representation of a cancer type and its associated mortality. Patient ages and gender distributions of CCLs were generally as expected, with some notable exceptions of female underrepresentation in certain disease types. Also, ethnicity information, while largely incomplete, suggests that African American and Hispanic patients may be severely underrepresented in these screens. Nearly all genes were targeted in the genetic perturbations screens, but the compounds used for the drug screens target less than half of known cancer drivers, likely reflecting known limitations in our drug design capabilities. Finally, we discuss recent developments in the field and the promise they hold for enabling future screens to overcome previous limitations and lead to new breakthroughs in cancer treatment.

Keywords: Biomarkers; Cancer; Cell lines; Drug screens; Genetic perturbation screens; Pharmacogenomics.