CRISPR screens map cancer vulnerabilities across driver mutations

Synthetic lethality enables targeted treatment of cancers harbouring loss-of-function mutations in tumour suppressors or gain-of-function alterations in oncogenes that resist conventional drug approaches. The researchers performed genome-wide CRISPR-Cas9 knockout screens using functionally validated isogenic cell line pairs to map dependencies across 15 cancer driver alterations, including FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, and chromosomal losses at 18q and 13q.

The findings were compared with large-scale cancer dependency data from DepMap, revealing both overlapping and isogenic-specific hits. Key validations include ARID1Adependency on GFPT1 glutaminase activity (not isomerase function), STK11 synthetic lethality with MARK2 kinase, and FBXW7 vulnerability to PKMYT1 inhibition across truncating and missense hotspot mutations. Additionally, CCNE1-amplified cells showed dependency on the anaphase-promoting complex ubiquitin-conjugating enzymes UBE2C and UBE2S. In vivo studies confirmed several interactions, demonstrating the therapeutic potential of existing PKMYT1 inhibitors and highlighting opportunities to develop novel targeted therapies.

The study was led by Alejandro Álvarez-Quilón and Jordan Young at Repare Therapeutics (now at DCx Biotherapeutics and AstraZeneca, respectively). The work was published on bioRxiv on 25 January 2026.