AKT1 belongs to a family of serine-threonine protein
kinases which also includes AKT2 and AKT3.
AKT1 plays a key role in multiple cell processes, including growth, proliferation, survival,
and angiogenesis. AKT1 acts as a downstream mediator of phosphatidylinositol 3-kinase (PI3K; Figure
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: Lovly, C., L. Horn, W. Pao. 2015. AKT1. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
AKT1 in Non-Small Cell Lung Cancer (NSCLC)
Somatic mutations in AKT1 have
been found in ~ 1% of all NSCLC (Bleeker et al. 2008; Do et al. 2008;
Malanga et al. 2008),
in both adenocarcinoma and squamous cell carcinoma histology. Preclinical data have shown
that the presence of this mutation results in cellular transformation in vitro and in
vivo (Carpten et al. 2007).
Specific clinical characteristics of lung cancer patients harboring AKT1 mutations
have yet to be described.
In the vast majority of cases, AKT1 mutations
are non-overlapping with other oncogenic mutations
found in NSCLC (e.g., EGFR mutations, ALK rearrangements, etc.).
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. AKT1 in Non-Small Cell
Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/akt1/
(Updated June 18).
Last Updated: June 18, 2015
AKT1 c.49G>A (E17K) Mutations in Non-Small Cell Lung Cancer (NSCLC)
The E17K mutation results in an amino acid change at position 17 in AKT1,
from a glutamic acid (E) to a lysine (K). This mutation
occurs within the pleckstrin homology domain (PHD) of AKT1 (Figure 1) and results in
activation of the phosphatidylinositol 3-kinase (PI3K) pathway. In vitro studies suggest
that the AKT1 E17K mutation is less
sensitive than wild type AKT1 to inhibition by the experimental AKT inhibitor VIII,
a non-ATP competitive agent which requires a functional pleckstrin homology domain (Carpten et al.
2007). Other AKT inhibitors are in development.
a In preclinical experiments using a cell line harboring BRAF V600E and
AKT1 E17K mutations, the AKT1 E17K mutation was associated with sensitivity
to GSK2141795B (a tool compound related to the AKT1 inhibitor uprosertib, GSK214179; Lassen et al.
b The role of AKT1 mutations
for selecting/prioritizing anti-cancer treatment is unknown at this time. However, it
should be noted that AKT1 mutations are usually found in tumors wild type for EGFR,
ALK, and other driver mutations.
Figure 1. Schematic of AKT1 E17K mutation. Functional domains of AKT1 are
depicted. PHD: pleckstrin homology domain. RD: regulatory domain.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. AKT1 c.49G>A (E17K)
Mutations in Non-Small Cell Lung Cancer
(NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/akt1/23/
(Updated October 7).
Last Updated: October 7, 2015
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