• What is PIK3CA?
  • PIK3CA in Lung Cancer
  • PIK3CA c.1633G>A (E545K)
  • 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/lung-cancer/pik3ca/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

PIK3CA in Non-Small Cell Lung Cancer (NSCLC)

Somatic mutations in PIK3CA have been found in 1–3% of all NSCLC (COSMICKawano et al. 2006; Samuels et al. 2004). These mutations usually occur within two "hotspot" areas within exon 9 (the helical domain) and exon 20 (the kinase domain). PIK3CA mutations appear to be more common in squamous cell histology compared to adenocarcinoma (Kawano et al. 2006) and occur in both never smokers and ever smokers. PIK3CA mutations can co-occur with EGFR mutations (Kawano et al. 2006; Sun et al. 2010). In addition, PIK3CA mutations have been detected in a small percentage (~5%) of EGFR-mutated lung cancers with acquired resistance to EGFR TKI therapy (Sequist et al. 2011).

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. PIK3CA in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/pik3ca/ (Updated June 18).

Last Updated: June 18, 2015

PIK3CA c.1633G>A (E545K) Mutation in Non-Small Cell Lung Cancer

Properties
Location of mutation Helical domain; Exon 10 (coding exon 9)
Frequency of PIK3CA mutations in NSCLC 1–3% (COSMICKawano et al. 2006; Samuels et al. 2004)
Frequency of E545K mutations in PIK3CA-mutated NSCLC 26.7% (COSMIC)
Implications for Targeted Therapeutics
Response to PI3K inhibitors Unknown at this timea
Response to dual PI3K/mTOR inhibitors Unknown at this timeb
Response to AKT inhibitors Unknown at this time
Response to EGFR TKIs Unknown at this timec
Response to anti-EGFR antibodies Unknown at this time

The E545K mutation results in an amino acid substitution at position 545 in PIK3CA, from a glutamic acid (E) to a lysine (K). This mutation occurs within the highly conserved helical 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).

Specific clinical characteristics of lung cancer patients harboring PIK3CA E545K mutations have yet to be described, and clinical responses of patients harboring a PIK3CA E545K lung tumor associated mutation to PIK3CA, AKT, and/or mTOR inhibitors are unknown at this time.

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.

b Lung cancer cell lines harboring PIK3CA activating mutations are sensitive to the dual PIK3CA/mTOR inhibitor, PI-103 (Zou et al. 2009). In addition, the dual PI3K/mTOR inhibitor, NVP-BEZ235, has shown potent anti-tumor activity in mice genetically engineered to express mutant PIK3CA (Engelman et al. 2008).

c Preclinical data have shown that introduction of activating PIK3CA mutations into EGFR-mutated lung cancer cell lines confers resistance to EGFR TKIs (Engelman et al. 2006). In addition, PIK3CA mutations have been detected in a small percentage (~5%) of EGFR-mutated lung cancers with acquired resistance to EGFR TKI therapy (Sequist et al. 2011).

pik3ca-e545k.png

Figure 1.
Schematic of PIK3CA E545K mutation. Functional domains of PIK3CA are depicted.

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Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2017. PIK3CA c.1633G>A (E545K) Mutation in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/pik3ca/8/ (Updated January 13).

Last Updated: January 13, 2017

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