Open AccessFunctional KRAS mutations and a potential role for PI 3K/ AKT activation in Wilms tumors
Author(s) -
Polosukhina Dina,
Love Harold D.,
Correa Hernan,
Su Zengliu,
Dahlman Kimberly B.,
Pao William,
Moses Harold L.,
Arteaga Carlos L.,
Lovvorn Harold N.,
Zent Roy,
Clark Peter E.
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12044
Subject(s) - kras , cancer research , protein kinase b , pi3k/akt/mtor pathway , wnt signaling pathway , signal transduction , chemistry , biology , mutation , microbiology and biotechnology , biochemistry , gene
Wilms tumor ( WT ) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/β‐catenin signaling. We previously showed that coordinate activation of Ras and β‐catenin accelerates the growth and metastatic progression of a murine WT model. Here, we show that activating KRAS mutations can be found in human WT . In addition, high levels of phosphorylated AKT are present in the majority of WT . We further show in a mouse model and in renal epithelial cells that Ras cooperates with β‐catenin to drive metastatic disease progression and promotes in vitro tumor cell growth, migration, and colony formation in soft agar. Cellular transformation and metastatic disease progression of WT cells are in part dependent on PI 3K/ AKT activation and are inhibited via pharmacological inhibition of this pathway. Our studies suggest both KRAS mutations and AKT activation are present in WT and may represent novel therapeutic targets for this disease.