Phosphatidylinositol-3-Kinase/Akt Signaling Pathway and Kidney Cancer, and the Therapeutic Potential of Phosphatidylinositol-3-Kinase/Akt Inhibitors

Purpose

The PI3K/Akt signaling pathway is activated by many cellular stimuli. It regulates fundamental cellular functions, including transcription, translation, proliferation, growth and survival. It also closely interacts with many other key pathways such as mTOR and, thus, is linked to angiogenesis. Disturbed activation of the PI3K/Akt pathway is associated with many human malignancies. We reviewed the available literature on PI3K/Akt and PI3K/Akt targeting drugs for renal cell carcinoma.

Materials and Methods

MEDLINE® and the proceedings of the main oncological meetings were extensively searched to identify the available literature on the role of this pathway in renal cell carcinoma pathogenesis, and on preclinical and clinical activity of compounds specifically targeting this pathway. Clinical data and perspectives on several compounds at different stages of development were also reviewed.

Results

Cumulative evidence links PI3K/Akt alterations with renal cell carcinoma. Thus, renal cell carcinoma is an ideal setting in which to test compounds specifically targeting this pathway. Several PI3K/Akt inhibitors are currently under preclinical and early clinical development as anticancer agents but only perifosine (Keryx Biopharmaceuticals, New York, New York) appears to be at a more advanced stage, having been tested with promising results alone or combined with other molecularly targeted agents.

Conclusions

The PI3K/Akt pathway has a pivotal role in renal cell carcinoma pathogenesis and, thus, represents an ideal target for therapeutic intervention. Of the several compounds in early phases of development only perifosine has already proved to be clinically active. Thus, it should be considered an extremely interesting drug to be used alone or in combination.

Key Words: kidney, carcinoma, renal cell, D 21266, 1-phosphatidylinositol 3-kinase, mTOR protein

Abbreviations and Acronyms: 17-HWT, 17-hydroxy-wortmannin, APC, alkylphosphocholine, ERK, extracellular regulated kinase, GSK3, glycogen synthase kinase-3, HIF, hypoxia-inducible factor, IC₅₀, half maximum inhibitory concentration, MEK, mitogen-activated and extracellular signal-regulated kinase, MTD, maximum tolerated dose, mTOR, mammalian target of rapamycin, mTORC, mTOR complex, NFκB, nuclear factor κB, PDK, 3′-phosphoinositide-dependent kinase, PI, phosphatidylinositol, PI-3,4,5-P₃, PI-3,4,5-triphosphate, PI3K, PI-3-kinase, PKB, protein kinase B, PTEN, phosphatase and tensin homolog deleted on chromosome 10, RCC, renal cell carcinoma, VEGF, vascular endothelial growth factor