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
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 (EOC)
|EOC Overall||Type I||Type II|
|Gene Mutation||Low Grade Serous||Clear Cell||Endometrioid||Mucinous||High Grade Serous|
|PIK3CA||6.7% (Campbell, Russell, and Phillips 2005; Levine et al. 2005; Wang et al. 2005)||5% (Nakayama et al. 2006)||20–33% (Campbell et al. 2004; Kuo et al. 2009)||20% (Campbell et al. 2004)||Rare||<1% (TCGA 2011)|
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).
|Gene||Exon||Location||Amino Acid Position||Amino Acid Change||Nucleotide Change||Frequency Among PIK3CA-Mutated Ovarian Cancer|
Last Updated: December 3, 2012
|Location of mutation||Kinase domain (exon 20)|
|Frequency of PIK3CA mutation||31% of PIK3CA-mutated ovarian cancers (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 dual PI3K/mTOR inhibitors||Unknown at this time|
The H1047R mutation results in an amino acid substitution at position 1047 in PIK3CA, from a histidine (H) to an arginine (R). This mutation occurs within the kinase 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).
a Preclinical and targeted Phase I studies suggest the main activity of PI3K pathway inhibitors will be limited to tumors with PIK3CA mutations (Janku et al. 2012).
Last Updated: June 1, 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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