Class IA phosphoinositide 3-kinase isoforms and human tumorigenesis: implications for cancer drug discovery and development.
OBJECTIVE
The phosphoinositide 3-kinases are lipid kinases that are activated in response to external factors. They regulate a number of intracellular signaling pathways involved in cell motility, metabolism, survival, and growth. This review summarizes the current knowledge about specific contributions of Class IA phosphoinositide 3-kinases to tumorigenesis and presents a rationale for the development of isoform-specific inhibitors.


RESULTS
In the last decade, the Class IA phosphoinositide 3-kinases have gained considerable attention as drug targets for the treatment of cancer. Indeed, pan-phosphoinositide 3-kinase inhibitors are being evaluated in early phases of clinical trials for the treatment of multiple human malignancies. Accumulating evidence suggests that selectively targeting individual isoforms is also possible. However, the patient population that is most likely to benefit from such selective compounds remains to be elucidated.


CONCLUSIONS
Given the importance of the phosphoinositide 3-kinase pathway in the initiation and maintenance of human tumors, drugs that effectively target its constituents will be an invaluable addition to the arsenal of anticancer therapeutics. However, to fully capitalize on the central role of this pathway in malignancy, we must first fully understand the nuances of its multiple players.
Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02319, USA. susan.wee@novartis.com
Susan
S
Wee
Christoph
C
Lengauer
Dmitri
D
Wiederschain
D000970:Antineoplastic Agents / Q000627:therapeutic use; D015197:Carcinogenicity Tests; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction
D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; C486018:PIK3CD protein, human