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 signaling pathway is active in most RCC. The activation of PI3-kinase would be expected to drive protein and lipid synthesis through 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-kinase in 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 inhibitors of mTOR as well and it is likely that these agents will prove particularly useful in the treatment of RCC.