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

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 WTs. 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 is in part dependent on PI3K/AKT activation and is abrogated 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.

Molecular oncology. 2017 Feb 11 [Epub ahead of print]

Dina Polosukhina, Harold D Love, Hernan Correa, Zengliu Su, Kimberly B Dahlman, William Pao, Harold L Moses, Carlos L Arteaga, Harold N Lovvorn, Roy Zent, Peter E Clark

Department of Urologic Surgery, Vanderbilt University Medical Center., Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center., Vanderbilt-Ingram Cancer Center., Department of Cancer Biology, Vanderbilt University Medical Center., Department of Medicine (Hematology-Oncology), Vanderbilt University Medical Center., Department of Pediatric Surgery, Vanderbilt University Medical Center.