The E545G mutation results in an amino acid substitution at position 545 in PIK3CA, from a glutamic acid (E) to a glycine (G). This mutation occurs within the highly conserved helical domain (Figure 1). Mutant PIK3CA proteins have increased catalytic activity resulting in enhanced downstream signaling and oncogenic transformation in vitro (Kang, Bader, and Vogt 2005).

Preclinical studies suggest the main activity of PI3K pathway inhibitors will be limited to tumors with PIK3CA mutations (Bachman et al. 2004; O'Brien et al. 2010; She et al. 2008). A phase I dose-escalation clinical trial of a pan-class I PI3K inhibitor in patients with advanced solid tumors—primarily colorectal, breast, and lung—showed preliminary antitumor activity (Bendell et al. 2011). Clarke and Workman (2012) note that PI3K inhibitors are being actively investigated in phase IB and II clinical trials.

PIK3CA mutations may be a potential biomarker in identifying rectal cancer patients with an increased risk for local recurrences (He et al. 2009).

^a PIK3CA mutations may be associated with clinical resistance to EGFR-targeted monoclonal antibodies, but there have been conflicting results (De Roock et al. 2010; Prenen et al. 2009; Sartore-Bianchi et al. 2009).

Figure 1. Schematic of PIK3CA E545G mutation. Functional domains of PIK3CA are depicted.