Abstract C007: A high-throughput screen to identify effective and translationally-relevant drug combinations for breast, colorectal, and pancreatic cancers
Authors: Coker Elizabeth A , Jaaks Patricia , Vis Daniel J , Aben Nanne , Barthorpe Syd , Meer Dieudonne van der , Lightfoot Howard , Wessels Lodewyk , Garnett Mathew ,   GDSC Screening Team
Published: March 2020

Abstract
Drug combinations offer a solution to two major issues faced by oncologists, drug resistance and tumour heterogeneity, but identifying the optimum combination of drugs for distinct molecular contexts remains challenging. This is particularly true for cancers where limited targeted therapies are available, for example pancreatic or KRAS-mutant colorectal cancers. We have established a high-throughput, systematic platform for screening large numbers of drug combinations in cell line panels. This includes 650 combinations in 48 colorectal cell lines, over 1,300 combinations in 52 breast cancer cell lines, covering all subtypes of the disease, and 650 combinations in 30 pancreatic cell lines. Combinations are screened in an anchor-library format, with an anchor drug used at two fixed concentrations, combined with the library drug at seven discontinuous concentrations. Drugs were chosen on a per-tissue basis, considering existing standards of care, known genomic features and core tissue pathways. We have prioritised drugs that are currently FDA-approved or are in late-stage clinical trials to ensure maximum clinical relevance of our data. Our screen presents response data for over 100,000 drug combination-cell line pairs, plus single agent drug sensitivities for over 4,800 single agent-cell line pairs. Combinations are classified as effective based on their resultant change in cell viability (ΔEMax) and change in drug sensitivity (ΔIC50). Drug combinations are ranked and prioritised based on potency, number of sensitive cell lines, and clinical relevance, i.e. use of FDA-approved drug(s). Validation of synergistic drug combinations, including using alternative inhibitors of promising target combinations, is ongoing. By screening combinations at this scale, we are able to perform statistically-powerful biomarker analysis, including integration with genomic, transcriptomic and proteomic data, and also clinical classifications such as PAM50 status. This study represents one of the largest drug combination screens performed to date, and focuses on two tissues for which targeted drug therapies are currently limited: pancreatic cancer and colorectal cancer. The third tissue studied, breast, represents a highly heterogenous cancer, meaning that selecting appropriate drug combinations is particularly challenging. We have ranked and prioritised effective drug combinations and identified biomarkers for the molecular contexts in which certain combinations are effective. We are currently validating combinations both in-house and with collaborators.
Citation Format: Elizabeth A Coker, Patricia Jaaks, Daniel J Vis, Nanne Aben, Syd Barthorpe, Dieudonne van der Meer, Howard Lightfoot, Lodewyk Wessels, Mathew Garnett, GDSC Screening Team. A high-throughput screen to identify effective and translationally-relevant drug combinations for breast, colorectal, and pancreatic cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C007. doi:10.1158/1535-7163.TARG-19-C007