• What is PIK3CA?
  • PIK3CA in Ovarian Cancer
  • Clinical Trials

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 (COSMICSamuels et al. 2004)

 

mapk-pk13.png

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.padiracinnovation.org/content/disease/ovarian-cancer/pik3ca/?tab=0 (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 (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 (COSMIC)
PIK3CA 9 Helical domain E542 p.E542K c.1624G>A 10.2%
E545 p.E545K c.1633G>A 12.6%
Q546 p.Q546K c.1636C>A 1.8%
20 Kinase Domain H1047 p.H1047R c.3140A>G 41.4%
p.H1047L c.3140A>T​ 2.8%

​​​​

Contributors: Dineo Khabele, M.D.

Suggested Citation: Khabele, D. 2015. PIK3CA in Ovarian Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/ovarian-cancer/pik3ca/ (Updated August 28).

Last Updated: August 28, 2015

My Cancer Genome has released its new and improved cancer clinical trials search tool on our beta website. Please visit beta.padiracinnovation.org to check it out!

Disclaimer: The information presented at padiracinnovation.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.