• What is AKT1?
  • AKT1 in Colorectal Cancer
  • AKT1 c.49G>A (E17K)
  • Clinical Trials

AKT1

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 1).

mapk-pi3k

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

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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. 2015. AKT1. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/akt1/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

AKT1 in Colorectal Cancer

Somatic mutations in AKT1 have been found in <1–6% of all colorectal cancer (Carpten et al. 2007; COSMIC; Fumagalli et al. 2008; Kim et al. 2008). In colorectal cancer, the only AKT1 mutation observed up to this time is the E17K mutation, which has also been observed in other types of cancer. This mutation in the Pleckstrin homology domain alters the ligand binding site and leads to constitutive kinase activity. Preclinical data have shown that the presence of this activating mutation results in cellular transformation in vitro and in vivo (Carpten et al. 2007). Specific clinical characteristics of colorectal cancer patients harboring AKT1 mutations have yet to be described. AKT1 mutations and PTEN mutations appear to be mutually exclusive. Likewise, AKT1 mutations and PI3K mutations appear to be mutually exclusive.​

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2015. AKT1 in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/akt1/ (Updated June 18).

Last Updated: June 18, 2015

AKT1 c.49G>A (E17K) Mutation in Colorectal Cancer

Properties
Location of mutation Pleckstrin homology domain (exon 4)
Frequency of AKT1 mutations in colorectal cancer <1–6%(Carpten et al. 2007; COSMIC; Fumagalli et al. 2008; Kim et al. 2008)​
Frequency of E17K mutations among AKT1-mutated colorectal cancer 80% (COSMIC)
Implications for Targeted Therapeutics
Response to AKT inhibitors Unknown at this time
Response to EGFR TKIs Unknown at this time
Response to anti-EGFR antibodies Unknown at this time
Response to PI3K inhibitors Unknown at this time

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.

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 PIK3CA and without PTEN loss (Carpten et al. 2007).

akt1-e17k.png 

Figure 1. Schematic of AKT1 E17K mutation. Functional domains of AKT1 are depicted. PHD: pleckstrin homology domain. RD: regulatory domain.

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Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2015. AKT1 c.49G>A (E17K) Mutation in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/akt1/23/ (Updated February 18).

Last Updated: February 18, 2015

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