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

Nat Med
Authors
Keywords
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.

Year of Publication
2015
Journal
Nat Med
Volume
21
Issue
1
Pages
71-5
Date Published
2015 Jan
ISSN
1546-170X
URL
DOI
10.1038/nm.3751
PubMed ID
25485910
PubMed Central ID
PMC4289115
Links
Grant list
1R01CA183947 / CA / NCI NIH HHS / United States
R01 CA183974 / CA / NCI NIH HHS / United States
R00 CA151457 / CA / NCI NIH HHS / United States
K08 CA181340 / CA / NCI NIH HHS / United States
R01 CA178397 / CA / NCI NIH HHS / United States
5R00CA151457 / CA / NCI NIH HHS / United States
F30 CA186477 / CA / NCI NIH HHS / United States
T32 GM071338 / GM / NIGMS NIH HHS / United States