PIK3CA
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.
Related Pathways
Contributors: Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014), Christine M. Lovly, M.D., Ph.D.
Suggested Citation: Horn, L., W. Pao, C. Lovly. 2015. PIK3CA. My Cancer Genome https://www.mycancergenome.org/content/disease/breast-cancer/pik3ca/?tab=0 (Updated December 7).
Last Updated: December 7, 2015
PIK3CA in Breast Cancer
Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.
Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. PIK3CA in Breast Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/breast-cancer/pik3ca/ (Updated August 28).
Last Updated: August 28, 2015
PIK3CA c.1634A>G (E545G) Mutation in Breast Cancer
Properties |
Location of mutation
|
Helical domain; Exon 10 (coding exon 9) |
Frequency of PIK3CA mutations in breast cancer |
26% (Saal et al. 2005; Stemke-Hale et al. 2008; O'Brien et al. 2010) |
Frequency of E545G mutation among PIK3CA-mutated breast cancers |
<1% |
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 HER2 inhibitors (lapatinib) |
Unknown at this time |
Response to anti-HER2 antibodies (trastuzumab) |
Unknown at this time |
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). Mutated PIK3CA proteins have increased catalytic activity resulting in enhanced downstream signaling and oncogenic transformation in vitro (Kang, Bader, and Vogt 2005).
a Multiple PI3K inhibitors, including BYL719, buparlisib (BKM120), taselisib (GDC0032), and GSK2636771, are under investigation in patients with PIK3CA-mutated or PTEN-mutated solid tumors. Results from several trials of buparlisib have been reported: from these trials, it is not apparent that PIK3CA mutation status affects therapeutic efficacy, and, overall, evidence for efficacy has been equivocal (Bendell et al. 2012; Hyman et al. 2015; Mayer et al. 2014). Additional trials of buparlisib as well as trials for other PI3K inhibitors are ongoing.

Figure 1. Schematic of PIK3CA E545G mutation. Functional domains of PIK3CA are depicted.
Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.
Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2017. PIK3CA c.1634A>G (E545G) Mutation in Breast Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/breast-cancer/pik3ca/13/ (Updated January 13).
Last Updated: January 13, 2017
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