Targeting PI3 kinase in cancer

The PI3K/Akt/mTOR pathway is the most frequently known activated aberrant pathway in human cancers. Pathologic activation can occur at multiple levels along the signaling pathway by a variety of mechanisms, including point mutations, amplifications, and inactivation of tumor suppressor genes. This pathway is also a known resistance pathway, as it can be activated by both receptor tyrosine kinases and other oncogenes. mTOR inhibitors were the first targeted molecules in this pathway, and have already been FDA-approved in multiple indications. Because of the broad potential applications of inhibiting this pathway upstream of mTOR, multiple compounds targeting PI3K are in development. In this review, we discuss the clinical development of these inhibitors, including dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-selective PI3K inhibitors. Common adverse events, including rash, nausea, vomiting, diarrhea, and hyperglycemia, have created a narrow therapeutic window for all classes of PI3K inhibitors. Furthermore, single agent clinical activity has also been limited, with the exception of isoform-selective inhibitors, particularly the PI3Kδ and PI3Kγ inhibitors in hematologic malignancies. The future role of inhibitors of the PI3K/Akt/mTOR pathway in the clinical practice of oncology likely depends on the development of patient selection strategies and the results of combination trials that are currently ongoing.