title: Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors.
abstract: 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.
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Polosukhina
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Harold D
authors.initials: HD
authors.lastname: Love
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Hernan
authors.initials: H
authors.lastname: Correa
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Zengliu
authors.initials: Z
authors.lastname: Su
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.|Department of Medicine (Hematology-Oncology), Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Medicine (Hematology-Oncology), Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Medicine (Hematology-Oncology), Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Harold N
authors.initials: HN
authors.lastname: Lovvorn
authors.affiliation: Department of Medicine, Nephrology & Cancer Biology Division, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
mesh_terms: D000818:Animals; D001483:Base Sequence; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000473:pathology; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)
keywords: AKT; KRAS; Wilms tumor; β-catenin