title: Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer.
abstract: Approximately 70% of patients with non-small-cell lung cancer present with late-stage disease and have limited treatment options, so there is a pressing need to develop efficacious targeted therapies for these patients. This remains a major challenge as the underlying genetic causes of ~50% of non-small-cell lung cancers remain unknown. Here we demonstrate that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. By using this approach, we have identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation, suppresses constitutive activation of downstream signaling pathways, and results in specific killing of the lung cancer cells. Genomic profiling of patients with lung cancer is ushering in an era of personalized medicine; however, lack of actionable mutations presents a significant hurdle. Our study indicates that targeted genetic dependency screens will be an effective strategy to elucidate somatic variants that are essential for lung cancer cell viability.
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom.
authors.forename: Shameem
authors.initials: S
authors.lastname: Fawdar
authors.forename: Eleanor W
authors.initials: EW
authors.lastname: Trotter
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Stephenson
authors.forename: Franziska
authors.initials: F
authors.lastname: Hanke
authors.forename: Anna A
authors.initials: AA
authors.lastname: Marusiak
authors.forename: Zoe C
authors.initials: ZC
authors.lastname: Edwards
authors.forename: Sara
authors.initials: S
authors.lastname: Ientile
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.forename: Crispin J
authors.initials: CJ
authors.lastname: Miller
authors.forename: John
authors.initials: J
authors.lastname: Brognard
mesh_terms: D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D020935:MAP Kinase Signaling System; D009154:Mutation; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D054462:p21-Activated Kinases / Q000235:genetics*
chemical_list: C443802:PAK5 protein, human; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D054462:p21-Activated Kinases; D020930:MAP Kinase Kinase Kinases; C433243:MAP3K9 protein, human
keywords: MAPK pathway; driver mutations; siRNA screen; signal transduction