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

Iñigo Ayestaran; Ana Galhoz; Elmar Spiegel; Ben Sidders; Jonathan R Dry; Frank Dondelinger; Andreas Bender; Ultan McDermott; Francesco Iorio; Michael P Menden

doi:10.1016/j.patter.2020.100065

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

Patterns (N Y). 2020 Jul 2;1(5):100065. doi: 10.1016/j.patter.2020.100065. eCollection 2020 Aug 14.

Authors

Iñigo Ayestaran^{1

2}, Ana Galhoz^{1

3}, Elmar Spiegel¹, Ben Sidders⁴, Jonathan R Dry^{5

6}, Frank Dondelinger⁷, Andreas Bender⁸, Ultan McDermott⁴, Francesco Iorio^{9

10}, Michael P Menden^{1

3

11}

Affiliations

¹ Institute of Computational Biology, Helmholtz Zentrum München GmbH-German Research Center for Environmental Health, Neuherberg 85764, Germany.
² CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of Cambridge, Cambridge, UK.
³ Department of Biology, Ludwig-Maximilians University Munich, Martinsried 82152, Germany.
⁴ Research and Early Development, Oncology, AstraZeneca, Cambridge CB4 0WG, UK.
⁵ Research and Early Development, Oncology, AstraZeneca, Boston, MA 02451, USA.
⁶ Tempus Labs, Boston, MA, USA.
⁷ Centre for Health Informatics, Computation and Statistics, Lancaster Medical School, Lancaster University, Lancaster LA1 4YW, UK.
⁸ Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
⁹ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1RQ, UK.
¹⁰ Human Technopole, Palazzo Italia Via Cristina Belgioioso 171, Milano 20157, Italy.
¹¹ German Centre for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany.

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 EGFR^T790M 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.

Keywords: CRISPR; biomarker discovery; biostatistics; cancer; cancer cell lines; drug combinations; drug high-throughput screens; drug resistance; early drug discovery; precision medicine.