Base editing screens define the genetic landscape of cancer drug resistance mechanisms
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.
Authors
- Giuditta Illuzzi (ORCID: https://orcid.org/0000-0003-1358-8424)
- Magdalena E Strauß (ORCID: https://orcid.org/0000-0002-6089-8049)
- Sara F. Vieira (ORCID: https://orcid.org/0000-0002-1021-3021)
- Andrew Bassett (ORCID: https://orcid.org/0000-0003-1632-9137)
- Daniela Conticelli (ORCID: https://orcid.org/0000-0003-4661-9776)
- Emre Karakoç (ORCID: https://orcid.org/0000-0002-2324-8127)
- Mamta Sharma (ORCID: https://orcid.org/0000-0002-0140-2816)
- Cansu Dinçer (ORCID: https://orcid.org/0000-0003-2043-911X)
- Gabriele Picco (ORCID: https://orcid.org/0000-0001-8568-2781)
- John C. Marioni (ORCID: https://orcid.org/0000-0001-9092-0852)
- Vivien Veninga (ORCID: https://orcid.org/0000-0002-5166-5075)
- Shriram G. Bhosle (ORCID: https://orcid.org/0000-0002-7638-2899)
- Chiara M. Cattaneo (ORCID: https://orcid.org/0000-0002-8168-8649)
- Emile E. Voest (ORCID: https://orcid.org/0000-0001-8249-9586)
- Alex Watterson
- Jonas Koeppel (ORCID: https://orcid.org/0000-0003-1306-3994)
- Marie Moullet
- Leopold Parts (ORCID: https://orcid.org/0000-0002-2618-670X)
- Katrina McCarten (ORCID: https://orcid.org/0009-0008-4881-4456)
- Josep V. Forment (ORCID: https://orcid.org/0000-0002-7797-2583)
- Mathew J. Garnett (ORCID: https://orcid.org/0000-0002-2618-4237)
- Matthew A. Coelho (ORCID: https://orcid.org/0000-0003-3737-2468)
- Sarah Cooper
Institutions
- AstraZeneca (United Kingdom) (GB)
- European Bioinformatics Institute (GB)
- Vita-Salute San Raffaele University (IT)
- University of Exeter (GB)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Wellcome Sanger Institute (GB)
- The Netherlands Cancer Institute (NL)
- Open Targets (GB)
- Oncode Institute (NL)
- Candiolo Cancer Institute (IT)
- Genomics (United Kingdom) (GB)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- University of Turin (IT)
- Stanford University (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1038/s41588-024-01948-8
- Citations
- 44
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 10.29
Funders
- Wellcome