Identification of Intrinsic Drug Resistance and Its Biomarkers in High-Throughput Pharmacogenomic and CRISPR Screens

Ayestaran, I. and Galhoz, A. and Spiegel, E. and Sidders, B. and Dry, J.R. and Dondelinger, F. and Bender, A. and McDermott, U. and Iorio, F. and Menden, M.P. (2020) Identification of Intrinsic Drug Resistance and Its Biomarkers in High-Throughput Pharmacogenomic and CRISPR Screens. Patterns, 1 (5). ISSN 2666-3899

Abstract

High-throughput drug screens in cancer cell lines test compounds at low concentrations, thereby enabling the identification of drug-sensitivity biomarkers, while resistance biomarkers remain underexplored. Dissecting meaningful drug responses at high concentrations is challenging due to cytotoxicity, i.e., off-target effects, thus limiting resistance biomarker discovery to frequently mutated cancer genes. To address this, we interrogate subpopulations carrying sensitivity biomarkers and consecutively investigate unexpectedly resistant (UNRES) cell lines for unique genetic alterations that may drive resistance. By analyzing the GDSC and CTRP datasets, we find 53 and 35 UNRES cases, respectively. For 24 and 28 of them, we highlight putative resistance biomarkers. We find clinically relevant cases such as EGFRT790M mutation in NCI-H1975 or PTEN loss in NCI-H1650 cells, in lung adenocarcinoma treated with EGFR inhibitors. Interrogating the underpinnings of drug resistance with publicly available CRISPR phenotypic assays assists in prioritizing resistance drivers, offering hypotheses for drug combinations. Cancer drug resistance is the major challenge of modern oncology. Identifying resistance and its biomarkers will empower the next generation of precision medicines. High-throughput pharmacology screens in cancer cell lines have successfully identified drug-sensitivity biomarkers, but drug-resistance biomarkers are underexplored. Intrinsic drug-resistance events are often rare and experimentally indistinguishable from cytotoxicity or artifacts without prior knowledge. To address this, we investigate cell-line populations sensitized to a drug treatment (i.e., carrying established sensitivity biomarkers) and characterize those cell lines that do not respond as expected. We highlight unique genetic features harbored by these cell lines and confirm their linkage to drug resistance using CRISPR gene essentiality data. Our analysis and results pave the way for enhanced precision medicine, guide further CRISPR screens, and identify potential drug combinations to tackle resistance. Identifying cancer drug resistance and its biomarkers will empower the next generation of anti-cancer medicines, tailoring treatments to individual patients. Detecting drug resistance in high-throughput pharmacology screens is experimentally challenging. We present a computational framework identifying rare intrinsically resistant cancer cell lines. Our observations provide hypotheses for associated drug-resistance biomarkers, which we validate with independent CRISPR essentiality screens. Our results pave the way for enhancing cancer precision medicine and effective drug combinations to overcome resistance. © 2020 The Authors