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 D549N mutations among PIK3CA mutant colorectal cancers||~up to 0.4% (COSMIC)|
|Implications for Targeted Therapeutics|
|Response to PI3K inhibitors||Unknown at this timea|
|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 EGFR TKIs||Unknown at this time|
|Response to EGFR antibodies||Unknown at this timeb|
The D549N mutation results in an amino acid substitution at position 549 in PIK3CA, from an aspartic acid (D) to an asparagine (N). 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).
b A retrospective consortium analysis did not show a correlation among exon 9 mutations and response or survival in subjects treated with cetuximab plus chemotherapy (De Roock et al. 2010).
Figure 1. Schematic of PIK3CA D549N 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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