ABSTRACT
The reasons for the considerable interest in identifying and developing cancer agents that inhibit the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway are multiple. Activation of this pathway plays a pivotal role in essential cellular functions such as survival, proliferation, migration, and differentiation. Aberrant activation of the pathway contributes to tumorigenesis, tumor metastasis, and resistance to standard cancer therapy. Nonclinical studies suggest that specific inhibitors impede tumor cell growth or induce apoptosis, and combining inhibitors of the PI3K/Akt/mTOR pathway with standard cancer therapies can attenuate tumor resistance. Recent studies indicate that blocking PI3K-Akt activation underlies the therapeutic efficacy seen with a number of approved drugs, including imatinib (Gleevec Bcr-Abl inhibitor; Novartis, Basel, Switzerland), trastuzumab (Herceptin, Her2/neu antibody; Genentech, South San Francisco, California, U.S.A.), gefitinib (Iressa EGFR inhibitor; AstraZeneca, London, U.K.), and erlotinib (Tarceva EGFR inhibitor; OSI Pharmaceuticals, Melville, New York, U.S.A.). Small molecules designed to specifically target components of the pathway are now being developed as single agents and in combination with standard cancer therapy. The biology of the pathway and inhibitory agents under clinical development are described in this chapter.
