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.

Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

“…We have previously shown that when grafted orthotopically these cells grow into tumors, metastasize to the lung, and recapitulate many of the features of human WT. 33 Compared to placebo treated control, four weeks of pyrvinium treatment significantly reduced the size of the primary tumors (Figure 1). It also profoundly reduced the number and size of the lung metastases seen at necropsy (Figure 2).…”

“…To test whether pharmacologic inhibition of β-catenin transcription can inhibit growth and metastatic disease progression, we grafted murine renal epithelial cells with activating mutations of both Kras and β-catenin (Kras/Catnb cells) under the renal capsule of nude mice as previously described 33 . We have previously shown that when grafted orthotopically these cells grow into tumors, metastasize to the lung, and recapitulate many of the features of human WT.…”

“…The tumor weight was expressed as the total weight of the grafted kidney normalized to its contralateral control as previously described. 33 Lung metastases were manually counted after hematoxylin and eosin (H&E) staining using 3 serial sections at two different depths within the lung tissue (six sections for each lung per mouse).…”

miR-216b Post-Transcriptionally Downregulates Oncogene KRAS and Inhibits Cell Proliferation and Invasion in Clear Cell Renal Cell Carcinoma

“…KRAS activation can trigger several important signaling pathways, such as the PI3K/ AKT and MAPK/ERK pathways, most of which regulate cell proliferation and invasion [17][18][19][20]. Therefore, we investigated the possibility that miR-216b regulates those pathways by targeting KRAS.…”

Corrigendum to: Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors

“…The following disclosure has been added to the original article (Polosukhina et al ., ). Dr. Arteaga was on a Novartis Advisory Board at the time of publication, but the Board service was unrelated to this study.…”