Abstract
Phosphoinositide-3- kinase (PI3K) signaling regulates cellular proliferation, survival and metabolism, and its aberrant activation is one of the most frequent oncogenic events across human cancers. In the last few decades, research focused on the development of PI3K inhibitors, from preclinical tool compounds to the highly specific medicines approved to treat patients with cancer. Herein we discuss current paradigms for PI3K inhibitors in cancer therapy, focusing on clinical data and mechanisms of action. We also discuss current limitations in the use of PI3K inhibitors including toxicities and mechanisms of resistance, with specific emphasis on approaches aimed to improve their efficacy.