Base editing screens define the genetic landscape of cancer drug resistance mechanisms

Menée à l'aide de lignées cellulaires, d'une co-culture d'organoïdes de tumeurs et de lymphocytes T ainsi que d'une technique de criblage par mutagenèse utilisant la technologie d'édition CRISPR, cette étude met en évidence des variants régulant la sensibilité d'anticancéreux et identifie les mécanismes impliqués

Nature Genetics, sous presse, 2024, article en libre accès

Résumé en anglais

Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant that sensitizes lung cancer cells to EGFR inhibitors. Our variant-to-function map has implications for patient stratification, therapy combinations and drug scheduling in cancer treatment.