PIK3CA encodes the p110alpha protein which is a catalytic subunit of the class I PI 3-kinases (PI3K). Class I PI3K are heterodimeric molecules composed of a catalytic subunit and a regulatory subunit. There are three possible catalytic subunits p110alpha, beta or delta. Class I PI3K are linked to many cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. PI3K activity may lead in fine to the activation of the Akt/mTOR pathway. PTEN, a tumor suppressor inactivated in many cancers counteracts the action of PI3K.
Somatic mutations at the PIK3CA gene have been found in tumors and thus, it can be considered a bona fide oncogene. Most of the mutations cluster in hot spots within the helical (amino acids 539-546) or the catalytic (kinase, amino acids 1025-1050) domains. Mutations are point substitutions in more than 98% of cases. PIK3CA is one of the most frequently mutated genes in a wide variety of cancers, for example those affecting colon, breast, urinary tract, endometrium, stomach, cervix, ovary. Defects in PIK3CA are also a cause of seborrheic keratosis, a common benign skin tumor.
PIK3CA mutations lead to constitutive activation of p110alpha enzymatic activity and allow growth factor-independent growth. In addition, when expressed in normal cells, these mutations allow anchorage-independent growth, further attesting to their important role in cancer development. PIK3CA gene amplification has also been proposed as a mechanism for oncogene activation in some tumors (Angulo et al., 2008).
Because PIK3CA is considered an important oncogene implicated in the development of a wide variety of human cancers, efforts are now being directed towards the development of molecules that inhibit the activity of PI3K. PTEN is a tumor suppressor that counteracts the action of PI3K. Thus, the treatment with drugs that inhibit p110alpha activity would be also potentially efficient in patients whose tumors carry genetic alterations at PTEN.
Although they have been valuable in the past, the early and still frequently employed PI3K inhibitors, wortmannin and LY294002, have significant limitations as chemical tools.
mTOR is downstream the activity of PI3 kinases. However, the activity of mTOR inhibitors rapamycin and the rapalogs (rapamycin analogues, such as temsirolimus, everolimus and ridaforolimus - formerly known as deforolimus-) in cancer patients where the PI3K/Akt/mTOR pathway is frequently activated has been disappointing (Markman B. et al. 2010).
A series of compounds are currently in clinical development. ‘Pure’ PI3K inhibitors (both pan-PI3K –such as GDC-0941- and isoform-specific) target only p110; dual inhibitors (such as NVP-BEZ235) target both PI3K and mTOR. Other inhibitors target Akt.
References (open access):
PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Ligresti G, Militello L, Steelman LS, Cavallaro A, Basile F, Nicoletti F, Stivala F, McCubrey JA, Libra M. Cell Cycle. 2009 May 1;8(9):1352-8.