title: An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer.
abstract: KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.
authors.forename: Adrian
authors.initials: A
authors.lastname: Vallejo
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Perurena
authors.affiliation: University of Navarra, Center for Applied Medical Research, Proteomics, Genomics and Bioinformatics Core Facility, Pamplona 31010, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Guruceaga
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Martinez-Canarias
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Zandueta
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.
authors.forename: Karmele
authors.initials: K
authors.lastname: Valencia
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arricibita
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Gwinn
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Leanne C
authors.initials: LC
authors.lastname: Sayles
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Chuang
authors.affiliation: University of Navarra, Center for Applied Medical Research, Morphology Unit, Pamplona 31010, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Guembe
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bailey
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.|The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.|The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Biankin
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.|Clínica Universidad de Navarra, Department of Medical Oncology, Pamplona 31008, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Ponz-Sarvise
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.affiliation: Stanford Institute for Immunity, Transplantation and Infection, Stanford, California 94305, USA.|Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Purvesh
authors.identifier: 0000-0002-4143-4708
authors.initials: P
authors.lastname: Khatri
authors.affiliation: Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: E Alejandro
authors.initials: EA
authors.lastname: Sweet-Cordero
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.|University of Navarra, Department of Histology and Pathology, Pamplona 31008, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
authors.affiliation: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.|University of Navarra, Department of Histology and Pathology, Pamplona 31008, Spain.
authors.forename: Silve
authors.initials: S
authors.lastname: Vicent
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009154:Mutation; D009857:Oncogenes / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000099169:Fos-Related Antigen 1
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016283:Proto-Oncogene Proteins p21(ras); D000099169:Fos-Related Antigen 1; C117307:KRAS protein, human