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 mutations in PIK3CA have been found in 1–3% of all NSCLC (COSMIC; Kawano 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 mutant lung cancers with acquired resistance to EGFR TKI therapy (Sequist et al. 2011).
Last Updated: June 1, 2012
|Location of mutation||Kinase domain (exon 20)|
|Frequency of PIK3CA mutations in NSCLC||1–3% (COSMIC; Kawano et al. 2006; Samuels et al. 2004)|
|Frequency of H1047R mutations in PIK3CA-mutated NSCLC||12.9% (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 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 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).
Specific clinical characteristics of lung cancer patients harboring PIK3CA H1047R mutations have yet to be described, and clinical responses of patients harboring a PIK3CA H1047R lung tumor associated mutation to PIK3CA, AKT, and/or mTOR inhibitors are unknown at this time.
a 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.
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 has shown that introduction of activating PIK3CA mutants into EGFR mutant 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 mutant lung cancers with acquired resistance to EGFR TKI therapy (Sequist et al. 2011).
Figure 1. Schematic of PIK3CA H1047R mutation. Functional domains of PIK3CA are depicted.
Last Updated: November 30, 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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