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.
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.
Suggested Citation: Horn, L., W. Pao, C. Lovly. 2015. PIK3CA. My Cancer
(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 (COSMIC; Kawano et al.
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
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.3140A>T (H1047L) Mutation in Non-Small Cell Lung Cancer
|Location of mutation
Kinase domain; Exon 21 (coding
|Frequency of PIK3CA mutations in
||1–3% (COSMIC; Kawano et al.
et al. 2004)
|Frequency of H1047L mutations in
|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 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).
Specific clinical characteristics of lung cancer patients harboring PIK3CA H1047L mutations have yet to be described, and
clinical responses of patients harboring a PIK3CA H1047L 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).
Figure 1. Schematic of PIK3CA H1047L
mutation. Functional domains of PIK3CA are
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2017. PIK3CA c.3140A>T
(H1047L) Mutation in Non-Small Cell Lung
Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/pik3ca/10/
(Updated January 13).
Last Updated: January 13, 2017
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