Phosphatidyl 3-kinases (PI3K) are a family of lipid kinases involved in many cellular processes, including cell growth, proliferation, differentiation, motility, and survival. PI3K is a heterodimer composed of 2 subunits—an 85 kDa regulatory subunit (p85) and a 110 kDa catalytic subunit. The PIK3CA gene encodes p110α, one of the catalytic subunits.
PI3K converts PI(4,5)P2 [Phosphatidylinositol 4,5-bisphosphate] to PI(3,4,5)P3 [Phosphatidylinositol (3,4,5)-trisphosphate] on the inner leaflet of the cell membrane. PI(3,4,5)P3 recruits important downstream signaling proteins, such as AKT, to the cell membrane resulting in increased activity of these proteins.
Mutant PIK3CA has been implicated in the pathogenesis of several cancers, including colon cancer, gliomas, gastric cancer, breast cancer, endometrial cancer, and lung cancer (COSMIC; Samuels et al. 2004)
Figure 1. Schematic of the MAPK and PI3K pathways. . Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: June 1, 2012
These mutations usually occur within two "hotspot" areas within exon 9 (the helical domain) and exon 20 (the kinase domain).
|Gene||Exon||Location||Amino Acid Position||Amino Acid Change||Nucleotide Change||Frequency Among PIK3CA Mutant Colon Cancer (COSMIC)|
Last Updated: September 19, 2012
|Location of mutation||Helical domain (exon 9)|
|Frequency of PIK3CA mutations in colorectal cancer||10–30% (COSMIC; Samuels et al. 2004)|
|Frequency of E545A mutations among PIK3CA mutant colorectal cancers||1% (COSMIC)|
|Implications for Targeted Therapeutics|
|Response to PI3K inhibitors||Unknown at this time|
|Response to AKT inhibitors||Unknown at this time|
|Response to mTOR inhibitors||Unknown at this time|
|Response to PI3K/mTOR inhibitors||Unknown at this time|
|Response to anti-EGFR antibodies||Unknown at this timea|
The E545A mutation results in an amino acid substitution at position 545 in PIK3CA, from a glutamic acid (E) to an alanine (A). 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 E545A mutation. Functional domains of PIK3CA are depicted.
Last Updated: September 19, 2012
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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