• What is AKT1?
  • AKT1 in Breast 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/breast-cancer/akt1/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

AKT1 in Breast Cancer

Somatic mutations in AKT1 have been found in a fraction of breast cancers (see Table).

Gene Mutation Invasive Breast Cancer Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer HER2 positive Invasive Breast Cancer Triple-negative Invasive Breast Cancer
AKT1 4% (O'Brien et al. 2010) 3.2% (Stemke-Hale et al. 2008) <1% (Stemke-Hale et al. 2008)a <1% (Stemke-Hale et al. 2008)a

a small sample size <100 patients

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. AKT1 in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/akt1/ (Updated June 18).

Last Updated: June 18, 2015

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

Properties
Location of mutation Pleckstrin homology domain (exon 4)
Frequency of AKT1 mutations in breast cancer ~up to 4% (O'Brien et al. 2010)
Frequency of E17K mutation among AKT1-mutated breast cancers 100% (COSMIC​)​
Implications for Targeted Therapeutics
Response to PI3K inhibitors Unknown at this time
Response to AKT inhibitors Unknown at this timea
Response to mTOR inhibitors Unknown at this time
Response to PI3K/mTOR inhibitors Unknown at this time
Response to HER2 inhibitors (lapatinib) Unknown at this time
Response to anti-HER2 antibodies (trastuzumab) 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, both allosteric and catalytic, are in clinical development.

a In preclinical experiments using a cell line harboring BRAF V600E and AKT1 E17K mutations (note that there are no co-occurring AKT1 and BRAF variants in any breast cancer sample in cBioPortal), the AKT1 E17K mutation was associated with sensitivity to GSK2141795B (a tool compound related to the AKT1 inhibitor uprosertib, GSK214179; Lassen et al. 2014).

 

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: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. AKT1 c.49G>A (E17K) Mutation in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/akt1/23/ (Updated October 12).

Last Updated: October 12, 2015

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