PIK3CA mutations lead to constitutive activation of p110alpha enzymatic activity, stimulate AKT signaling, and allow growth factor-independent growth (Bader et al., 2005). In addition, when expressed in normal cells, these mutations allow anchorage-independent growth, further attesting to their important role in cancer development (Kang et al., 2005). PIK3CA somatic mutations are frequent in a variety of human primary tumors and cancer cell lines such as, among others, those of the colon, breast, and stomach (Samuels et al., 2004). However, in other tumors, i.e. those of the lung, head and neck, brain, endometrium, ovary, prostate, osteosarcoma and pancreas, hematopoietic malignancies, PIK3CA mutations are not as common (Angulo et al., 2008; Qiu et al., 2006; Muller et al., 2007; Samuels et al., 2004; Schonleben et al., 2006). PIK3CA gene amplification has also been proposed as a mechanism for oncogene activation in some tumors (Angulo et al., 2008). Because PIK3CA is now 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 (Garcia-Echeverria et al., 2008). These could be efficient in the treatment of those tumors carrying constitutive activation of PI3K pathway. PTEN is a well known tumor suppressor that counteracts the action of PI3K by dephosphorylating the phosphoinositide-3,4,5-trisphosphate (PIP3). Thus, the treatment with drugs that inhibit p110alpha activity would be also potentially efficient in patients whose tumors carry genetic alterations at PTEN.
It has recently been reported that activation of the PI3K pathway in breast tumors with concomitant ERBB2 gene amplification, either through PIK3CA mutations or PTEN inactivation, underlies trastuzumab resistance. These findings may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy (Berns et al., 2007).