| Autor: |
Jessica C Pickles, Barry Pizer, Darren Hargrave, Steven C. Clifford, Thomas S. Jacques, Aimee Avery, James M Barker, Amanda Smith, Matthew Bashton, James A Wood, Daniel Williamson, Simon Bailey, Matthew Selby, Stephen Lowis, Alicia del Carpio Pons, Bernadette Brennan, Patricia O’Hare, Sarah Batting, Martina Finetti, Stephen Crosier, Amy R Fairchild |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Popis: |
ATRTs have low mutation rates and few classically-actionable variants to direct molecularly targeted therapies; loss of SMARCB1 is the sole recurrent mutational event in >90% of ATRTs. We have designed and implemented a genome-scale strategy for target identification and prioritization in tumors devoid of significant actionable mutations. Re-expression of SMARCB1 causes ATRT cells to cease proliferation and differentiate; we therefore hypothesized that identifying and counteracting critical downstream SMARCB1-dependent events represents a primary route to therapeutic intervention. We identify such events using an integrated genome-wide approach encompassing genome-scale CRISPR/Cas9 functional screens (GeCKO screening; 122,411 sgRNAs) alongside expression/DNA methylation profiling of primary ATRTs and ATRT cells following SMARCB1 re-expression and/or treatment with demethylating agents. Cross-referencing these analyses, we use a rational selection algorithm, to identify critical tumorigenic genes/pathways and proceed to validate their ability to be targeted as therapeutic targets. Our strategy identifies, ranks and prioritizes multiple SMARCB1-dependent pathways/genes functionally essential to ATRT, and characteristic of the primary tumour; including those previously described (Rb/CDK4/6, SHH, MYC), those less well evidenced (mTOR, TGF-β, HGF, Stat3/Jak) and novel SMARCB1-dependent synthetic lethalities (NuA4 complex, PIM1). We also describe the repressive genome-wide effect of SMARCB1 mutation on the transcriptome, through altered SWI/SNF binding, associated histone marks and localized hypermethylation and the therapeutic possibilities implied therein. Data and web-based interactive analysis and visualization tools will be made publically available to help guide and benchmark future pre-clinical testing in ATRT. This study pinpoints SMARCB1-dependent therapeutic susceptibilities in MRTs with the capacity to inform future treatment strategies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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