title: Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.
abstract: Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.affiliation: 1] Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Adelmant
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shindoh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yoda
authors.affiliation: Department of Medicine III, Campus Grosshadern, Ludwig-Maximilians-University, and Helmholtz Center, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Weigert
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nadja
authors.initials: N
authors.lastname: Kopp
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shuo-Chieh
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sunhee S
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Huiyun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Tivey
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Jounce Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Kutlu G
authors.initials: KG
authors.lastname: Elpek
authors.affiliation: Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Card
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kira
authors.initials: K
authors.lastname: Gritsman
authors.affiliation: Division of Hematology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.affiliation: Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Javidi-Sharifi
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: 1] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Jaiswal
authors.affiliation: 1] Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: 1] Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053614:Janus Kinase 2 / Q000096:biosynthesis; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics
chemical_list: C516790:GNB1 protein, human; C578133:GNB2 protein, human; D044387:GTP-Binding Protein beta Subunits; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins