| First Author | Yoda A | Year | 2015 |
| Journal | Nat Med | Volume | 21 |
| Issue | 1 | Pages | 71-5 |
| PubMed ID | 25485910 | Mgi Jnum | J:227946 |
| Mgi Id | MGI:5704035 | Doi | 10.1038/nm.3751 |
| Citation | Yoda A, et al. (2015) Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance. Nat Med 21(1):71-5 |
| abstractText | Activating mutations in genes encoding G protein alpha (Galpha) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gbeta subunits have not been defined. Here we demonstrate that recurrent mutations in the Gbeta proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Galpha subunits as well as downstream effectors and disrupt Galpha interactions with the Gbetagamma dimer. Different mutations in Gbeta 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. |
