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.
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.
Suggested Citation: Horn, L., W. Pao, C. Lovly. 2015. PIK3CA. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
PIK3CA in Ovarian Cancer
Somatic alterations in PIK3CA have been found in a substantial fraction of ovarian cancers
(Samuels et al.
2004; COSMIC). Both genetic and biochemical data
suggest that activation of the PI3K/AKT survival pathway contributes to ovarian cancer
development and tumorigenesis.
PIK3CA amplifications are more common in type II high grade serous ovarian tumors (TCGA 2011). PTEN
loss is more common in type I ovarian tumors (Kurman and Shih
2011). The impact of these alterations on the virulence of ovarian cancer and
patient outcome is still under investigation. Prospective studies to confirm these findings
are in progress. Preclinical evidence exists for inhibitors of the PI3K pathway and novel
PI3K inhibitors are currently in clinical development. Frequencies of PIK3CA mutations in subtypes of ovarian cancer
are shown in table 1, and frequencies of specific PIK3CA mutations in ovarian cancer are shown in table 2.
Agents include PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR
inhibitors. Although these small molecules block different elements within the same cellular
signaling pathway, their differential
selectivity may have distinct therapeutic impact in patients with ovarian cancer. A recent
phase I study showed that ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors were
more sensitive to treatment than those without PIK3CA mutations
(Janku et al. 2012).
Table 1. Frequency of Somatic PIK3CA Gene
Mutations in Epithelial Ovarian Cancer
Table 2. Frequencies of specific mutations.
These mutations usually occur within two
"hotspot" areas within exon 9 (the helical domain) and exon 20 (the kinase domain).
Suggested Citation: Khabele, D. 2015. PIK3CA in Ovarian Cancer. My Cancer
(Updated August 28).
Last Updated: August 28, 2015
PIK3CA c.1624G>A (E542K) Mutation in Ovarian Cancer
|Location of mutation
||Helical domain; Exon 10 (coding exon 9)
|Frequency of PIK3CA mutations in
Russell, and Phillips 2005; Levine et al.
et al. 2005)
|Frequency of E542K mutation among
PIK3CA-mutated ovarian cancer
|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 dual PI3K/mTOR inhibitors
||Unknown at this time
The E542K mutation results in an amino acid substitution at position 542 in
PIK3CA, from a glutamic acid (E) to a lysine (K). This mutation
occurs within the helical domain (Figure 1). Mutant PIK3CA proteins have increased catalytic activity resulting in
enhanced downstream signaling and oncogenic transformation in vitro (Kang, Bader, and
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; Vansteenkiste
et al. 2015). Additional trials of buparlisib as well as trials for other PI3K
inhibitors are ongoing.
Figure 1. Schematic of PIK3CA E542K
mutation. Functional domains of PIK3CA are
Suggested Citation: Khabele, D. 2017. PIK3CA c.1624G>A (E542K) Mutation in Ovarian Cancer. My Cancer
(Updated January 13).
Last Updated: January 13, 2017
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