PI3K/Akt/mTOR Pathway: A Growth and Proliferation Pathway

The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway regulates numerous cellular processes such as growth, proliferation, cell cycle progression, motility, adhesion, and angio-genesis, and appears to be constitutively active in a majority of renal cell carcinoma (RCC). The integrity of the pathway is clearly vital to the survival and growth of RCC as pharmacologic inhibition of PI3K or Akt induces apoptosis in RCC tumor cells and tumor regression in vivo. These observations suggest that the PI3K/Akt/ mTOR pathway may be an attractive target for drug development in the treatment of RCC. The recently demonstrated clinical efficacy of inhibitors of mTOR supports this hypothesis and demonstrates the relevance of this pathway in RCC. As Akt activates numerous kinases, transcription factors and other proteins associated with cell growth and survival in addition to mTOR, it is possible even greater clinical responses may be achieved with agents that disrupt the PI3K/Akt/mTOR pathway upstream of mTOR. Concurrent with the development of inhibitors of PI3K or Akt for clinical application are efforts to identify predictive biomarkers of response to agents targeting elements of the PI3K/Akt/mTOR pathway so as to develop more individualized patient selection strategies. In this chapter, we will review the molecular biology of the PI3K/Akt/mTOR pathway, its relevance to RCC, and its potential as a therapeutic target in RCC.