title: CRISPR-Mediated Drug-Target Validation Reveals Selective Pharmacological Inhibition of the RNA Helicase, eIF4A.
abstract: Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti-neoplastic activity in preclinical settings. Among these are some rocaglate family members that are well tolerated in vivo, deplete eIF4F of its eIF4A helicase subunit, have shown activity as single agents in several xenograft models, and can reverse acquired resistance to MAPK and PI3K-mTOR targeted therapies. Herein, we highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Galicia-Vázquez
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mills
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Katigbak
authors.affiliation: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Oncology, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address: jerry.pelletier@mcgill.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001572:Benzofurans / Q000494:pharmacology*; D064113:CRISPR-Cas Systems / Q000235:genetics*; D016503:Drug Delivery Systems; D004351:Drug Resistance / Q000187:drug effects; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D015203:Reproducibility of Results; D014315:Triterpenes / Q000494:pharmacology
chemical_list: D001572:Benzofurans; D014315:Triterpenes; C489897:silvestrol; D039601:Eukaryotic Initiation Factor-4A
keywords: CRISPR/Cas9; chemical biology; eIF4A; rocaglates; translational control