Technology
The class I phosphatidylinositol-3-kinases (PI3Ks) are key regulators of diverse and critical cellular processes, including cell growth, survival and proliferation. There are four PI3K family members – PI3K alpha, beta, gamma and delta – and dysregulation of these proteins has been implicated in several diseases, notably various cancers and inflammatory disorders.
The PI3K and mTOR signaling network promotes a diverse range of cellular functions, including
cell growth, proliferation, survival and metabolism.
PI3K and Cancer
PI3K alpha and PI3K beta are widely expressed throughout the body. PI3K alpha activity is frequently elevated in tumor cells by mutation and/or gene amplification, and may play a role in growth and survival of many different tumor types. PI3K beta has also been associated with the growth and survival of cancer cells that are deficient in PTEN (a negative regulator of PI3K activity). PI3K can also be activated in tumor cells by other mechanisms, including receptor tyrosine kinase signaling and mutations in the RAS oncogene. In addition to regulating the growth, proliferation and survival of tumor cells, PI3K activity has been implicated in conferring resistance to chemotherapy, radiotherapy and receptor tyrosine kinase inhibitors. In contrast to the alpha and beta isoforms, PI3K delta is exclusively expressed in leucocytes and has been implicated in the growth and survival of various hematological malignancies. One of the most important signaling proteins downstream of PI3K is mTOR, which serves as an integrator of multiple cellular growth signals. In addition to PI3K-dependent growth factor signals, mTOR is regulated by cellular energy levels, nutrients and tissue oxygenation. Two mTOR signaling complexes with distinct functions have been identified, termed mTORC1 and mTORC2. Rapamycin and its various analogs (‘rapalogs’) are selective inhibitors of the mTORC1 complex, and have shown clinical activity in several tumor types. However, a negative feedback mechanism in cells may lead to activation of the PI3K pathway and thereby blunt the effect of these drugs. Therefore, dual inhibition of PI3K isoforms and mTOR is a promising approach to the treatment of various cancers.
PI3K and Inflammation
PI3K gamma and PI3K delta are exclusively expressed in leukocytes. PI3K gamma signals downstream of G-protein coupled receptors, whereas PI3K delta is associated with signaling by receptor tyrosine kinases and other cell surface receptors. Both isoforms are thought to have distinct but overlapping roles in various autoimmune and inflammatory diseases, including rheumatoid arthritis, allergy, asthma, chronic obstructive pulmonary disease and systemic lupus erythematosus. Hence, selective inhibitors of PI3K gamma and/or PI3K delta may have utility in treatment of these and other pathologies of the immune system.
