Targeting the PI3K/Akt/mTOR pathway in malignancy: rationale and clinical outlook.

The phosphatidylinositol 3-kinase (PI3K) pathway, including major downstream effectors Akt and mammalian target of rapamycin (mTOR), plays a critical role in malignant transformation and subsequent processes of growth, proliferation, and metastases. Not surprisingly, the PI3K/Akt/mTOR pathway has emerged as an attractive drug target and numerous agents directed against various elements of the pathway are currently in clinical development. While early clinical trials with the first generations of these agents have shown limited single-agent efficacy, efforts are now focused on the development of more specific inhibitors, patient selection strategies, and combinational approaches. In this review, we discuss the PI3K/Akt/mTOR pathway in cancer, the rationale for its emergence as a therapeutic target, and progress thus far in the clinical development of inhibitors targeting its various elements.