Reference Detail

Ref Type

Journal Article

PMID

(39424923)

Authors

Coelho MA, Strauss ME, Watterson A, Cooper S, Bhosle S, Illuzzi G, Karakoc E, Dinçer C, Vieira SF, Sharma M, Moullet M, Conticelli D, Koeppel J, McCarten K, Cattaneo CM, Veninga V, Picco G, Parts L, Forment JV, Voest EE, Marioni JC, Bassett A, Garnett MJ

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature genetics			2024 Oct 18		Nat Genet

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
MAP2K1	S194P	missense	unknown	MAP2K1 S194P lies within the protein kinase domain of the Map2k1 protein (UniProt.org). S194P has been demonstrated to confer resistance to Raf and Mek inhibitors in the context of BRAF V600E in culture (PMID: 39424923), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Sep 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E MAP2K1 Y130C	colorectal cancer	resistant	Cetuximab + Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Tafinlar (dabrafenib) and Erbitux (cetuximab) combination treatment inhibited senescence in a colorectal cancer cell line harboring BRAF V600E and expressing MAP2K1 Y130C in culture (PMID: 39424923).	39424923
BRAF V600E MAP2K1 S194P	colorectal cancer	resistant	Cetuximab + Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Tafinlar (dabrafenib) and Erbitux (cetuximab) combination treatment inhibited senescence in a colorectal cancer cell line harboring BRAF V600E and expressing MAP2K1 S194P in culture (PMID: 39424923).	39424923