Phosphoinositide 3-kinases as drug targets in cancer

The past two years have seen phosphoinositide 3-kinases (PI3Ks) move from being seen as potential targets for chemotherapeutics, to one of them--PI3Kalpha--being generally accepted as validated. A huge amount of work indicated that there was an important role for PI3Ks in tumour progression and, particularly, in the control of proliferation, survival and regulation of the potential oncogene PKB. These links were further strengthened by studies showing that the tumour suppressor, PTEN, is an antagonist of PI3K signalling and that somatic mutations of p110alpha (PIK3CA) are present in a variety of cancers. We now know that three of the most frequent mutations in cancer constitutively activate PI3Kalpha and, when expressed in cells, they drive the oncogenic transformation and chronic activation of downstream signalling by molecules such as PKB, S6K and 4E bp1 that is commonly seen in cancer cells. A large body of research into the cellular roles of PI3Ks has also further validated them as potential foci for cancer chemotherapy, with several additional PI3K effectors controlling cell proliferation and apoptosis having been described. Furthermore, molecules important to the processes of metastasis, development of multi-drug resistance, the 'Warburg effect', angiogenesis and cell growth (i.e. distinct to proliferation) have been found to depend upon, or to be driven by, PI3K activity.