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.
journal_name
Nat Medjournal_title
Nature medicineauthors
Yoda A,Adelmant G,Tamburini J,Chapuy B,Shindoh N,Yoda Y,Weigert O,Kopp N,Wu SC,Kim SS,Liu H,Tivey T,Christie AL,Elpek KG,Card J,Gritsman K,Gotlib J,Deininger MW,Makishima H,Turley SJ,Javidi-Sharifi N,Maciejewskidoi
10.1038/nm.3751subject
Has Abstractpub_date
2015-01-01 00:00:00pages
71-5issue
1eissn
1078-8956issn
1546-170Xpii
nm.3751journal_volume
21pub_type
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