Dual inhibition of PI3-kinase and mTOR in renal cell carcinoma.

Although PI3-kinase mutations are uncommon in renal cell carcinoma (RCC), the PI3-kinase/Akt signalingpathway is active in most RCC. The activation of PI3-kinase would be expected to drive protein and lipid synthesisthrough its effects on mTORC1 and SREBP1, respectively. PI3-kinase also activates numerous transcription factors (e.g.the FOXO family, c-myc, NF-κB) that regulate cell proliferation and viability. The consequences of blocking PI3-kinasein RCC are just now beginning to be elucidated and are expected to include effects on tumor cell proliferation,metabolism, and angiogenesis. Several PI3-kinase inhibitors currently undergoing clinical testing are active site inhibitorsof mTOR as well and it is likely that these agents will prove particularly useful in the treatment of RCC.