Identification of Intrinsic Drug Resistance and Its Biomarkers in High-Throughput Pharmacogenomic and CRISPR Screens.
Patterns (N Y)
; 1(5): 100065, 2020 Aug 14.
Article
em En
| MEDLINE
| ID: mdl-33205120
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.
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Base de dados:
MEDLINE
Tipo de estudo:
Diagnostic_studies
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article