CRISPR-enabled genetic screens identify synthetic lethal targets across frequently altered cancer drivers
Desjardins, J.; Bowlan, J.; Bernier, C.; Jain, S.; Goullet de Rugy, T.; Gallo, D.; Orcholski, M. E.; Laterreur, N.; Rajah, A.; Miller, J.; Lafontaine, J.; Bhaskaran, V.; Li, L.; Ling, A.; Leblanc, J. H.; Mathieu, M.-C.; Zinda, M.; Morris, S. J.; Durocher, D.; Zimmermann, M.; Roulston, A.; Veloso, A.; Fiore, C.; Alvarez-Quilon, A.; Young, J. T.
Show abstract
Synthetic lethality (SL) provides a treatment paradigm for targeting cancer with alterations in driver genes that are not conventionally druggable, including loss-of-function (LoF) mutations in tumor suppressor genes and gain-of-function (GoF) alterations in oncogenes. We undertook a series of genome-wide CRISPR screens using functionally validated isogenic cell lines and also conducted a large-scale SL analysis using data from the cancer dependency map (DepMap). We charted SL interactions across 15 genetic alterations characteristic of diseases with high incidence and unmet clinical need: FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, chromosome 18q loss, and chromosome 13q loss. We show validation of several SL interactions between tractable targets with cancer drivers, including ARID1A and the hexosamine biosynthetic pathway aminotransferase GFPT1, STK11 with CAMK protein kinase family members including MARK2, FBXW7 and the CDK1 regulatory kinase PKMYT1, and CCNE1 amplification and the anaphase promoting complex or cyclosome (APC/C). In summary, this study offers a rich resource of genetic interactions across cancer drivers enabling the discovery of new biological insights and drug targets for future therapeutic development.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer 98%
- A recurrent pathogenic BRCA2 truncating variant reveals a role for BRCA2-PCAF complex in modulating NF-κB-driven transcription 97%
- The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma. 97%
Similar papers in this journal
Similar papers in this journal
- Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sexchromosome encoded genes 97%
- Genome-wide identification and analysis of prognostic features in human cancers 97%
- Genetic dependencies associated with transcription factor activities in human cancer cell lines 96%
Similar papers in this journal
- Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance 96%
- Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma 96%
- Dissecting mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage 96%
Similar papers in this journal
- EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes 97%
- CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis 96%
- Combinatorial tumor suppressor inactivation efficiently initiates lung adenocarcinoma with therapeutic vulnerabilities 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.