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Nat Med. 2015 Jan;21(1):71-5. doi: 10.1038/nm.3751. Epub 2014 Dec 8.

Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
2
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.
3
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.
4
Department of Medicine III, Campus Grosshadern, Ludwig-Maximilians-University, and Helmholtz Center, Munich, Germany.
5
1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Jounce Therapeutics, Inc., Cambridge, Massachusetts, USA.
6
Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
7
Division of Hematology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
8
Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
9
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
10
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
11
Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA.
12
1] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
13
1] Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
14
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
15
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.

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.

Comment in

PMID:
25485910
PMCID:
PMC4289115
DOI:
10.1038/nm.3751
[Indexed for MEDLINE]
Free PMC Article

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