• What is PIK3CA?
  • PIK3CA in Colorectal Cancer
  • PIK3CA c.3140A>T (H1047L)
  • 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/colorectal-cancer/pik3ca/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

PIK3CA in Colorectal Cancer

Somatic mutations in PIK3CA have been found in 10–30% of colorectal cancers (COSMICSamuels et al. 2004).

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 Colon Cancer (COSMIC)
PIK3CA 9 Helical domain E542 p.E542K c.1624G>A 17%
E545 p.E545K c.1633G>A 28%
p.E545Q c.1633G>C 0.3%
p.E545G c.1634A>G 2.1%
p.E545V c.1634A>T 0.2%
Q546 p.Q546K c.1636C>A 4.2%
p.Q546E c.1636C>G 0.3%
p.Q546P c.1637A>C 0.2%
p.Q546R c.1637A>G 0.5%
p.Q546L c.1637A>T 0.3%​
D549 p.D549N c.1645G>A 0.4%
20 Kinase Domain H1047 p.H​1047R c.3140A>G 21%
p.H1047L c.3140A>T 4.0%

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Contributors: Alberto Bardelli, Ph.D.

Suggested Citation: Bardelli, A. 2015. PIK3CA in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/pik3ca/ (Updated August 28).

Last Updated: August 28, 2015

PIK3CA c.3140A>T (H1047L) Mutation in Colorectal Cancer

Properties
Location of mutation Kinase domain; Exon 21 (coding exon 20)
Frequency of PIK3CA mutations in colorectal cancer 10–30% (COSMIC; Samuels et al. 2004)​
Frequency of H1047L mutations among PIK3CA-mutated colorectal cancers ~up to 4% (COSMIC)
Implications for Targeted Therapeutics
Response to PI3K inhibitors Unknown at this time
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 anti-EGFR antibodies Unknown at this time​a

The H1047L mutation results in an amino acid substitution at position 1047 in PIK3CA, from a histidine (H) to a leucine (L). This mutation occurs within the highly conserved 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).

Preclinical studies suggest the main activity of PI3K pathway inhibitors will be limited to tumors with PIK3CA mutations (Bachman et al. 2004; O'Brien et al. 2010; She et al. 2008). A phase I dose-escalation clinical trial of a pan-class I PI3K inhibitor in patients with advanced solid tumors—primarily colorectal, breast, and lung—showed preliminary antitumor activity (Bendell et al. 2011). Clarke and Workman (2012) note that PI3K inhibitors are being actively investigated in phase IB and II clinical trials.

PIK3CA mutations may be a potential biomarker in identifying rectal cancer patients with an increased risk for local recurrences (He et al. 2009).

a PIK3CA mutations may be associated with clinical resistance to EGFR-targeted monoclonal antibodies, but there have been conflicting results (De Roock et al. 2010Prenen et al. 2009Sartore-Bianchi et al. 2009).

 

pik3ca-h1047l.png

Figure 1.
Schematic of PIK3CA H1047L mutation. Functional domains of PIK3CA are depicted.

Contributors: Alberto Bardelli, Ph.D.

Suggested Citation: Bardelli, A. 2017. PIK3CA c.3140A>T (H1047L) Mutation in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/pik3ca/10/ (Updated January 13).

Last Updated: January 13, 2017

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