• What is AKT1?
  • AKT1 in Lung 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/lung-cancer/akt1/?tab=0 (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.).

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 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)

Properties
Location of mutation Pleckstrin homology domain (exon 4)
Frequency of AKT1 mutations in NSCLC ~1% (Bleeker et al. 2008; Do et al. 2008; Malanga et al. 2008)
Frequency of E17K mutations in AKT1-mutated NSCLC 88% (COSMIC)
Implications for Targeted Therapeutics
Response to AKT inhibitors Unknown at this timea
Response to EGFR TKIs Unknown at this timeb
Response to anti-EGFR antibodies Unknown at this time​b

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. 2014).

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.

akt1-e17k.png

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

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 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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