Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors.

Polosukhina D, Love HD, Correa H, Su Z, Dahlman KB, Pao W, Moses HL, Arteaga CL, Lovvorn HN, Zent R, Clark PE
Mol Oncol. 2017 11 (4): 405-421

PMID: 28188683 · PMCID: PMC5378659 · DOI:10.1002/1878-0261.12044

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 PI3K/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.

© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

MeSH Terms (18)

Animals Base Sequence beta Catenin Cell Movement Cell Proliferation Cell Transformation, Neoplastic Disease Progression Enzyme Activation Humans Immunohistochemistry Kidney Neoplasms Mice, Inbred C57BL Mutation Neoplasm Metastasis Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins p21(ras) Wilms Tumor

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