AKT1E17K Activates Focal Adhesion Kinase and Promotes Melanoma Brain Metastasis

Kircher, David A.; Trombetti, Kirby A.; Silvis, Mark R.; Parkman, Gennie L.; Fischer, Grant M.; Angel, Stephanie N.; Stehn, Christopher M.; Strain, Sean C.; Grossmann, Allie H.; Duffy, Keith L.; Boucher, Kenneth M.; McMahon, Martin; Davies, Michael A.; Mendoza, Michelle C.; VanBrocklin, Matthew W.; Holmen, Sheri L.

doi:10.1158/1541-7786.mcr-18-1372

Cited by 49 publications

(43 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Almost all (94.3%, 33/35) of AKT1 mutations were identified in HR + /HER2breast tumors, with only one typical hotspot mutation. AKT1 E17K is a single amino acid mutation in the pleckstrin homology (PH) domain of the AKT1 protein, which has been reported to function as a carcinogenic driver mutation in breast cancer and other solid cancers [18,19]. In our cohort, breast cancers with AKT1 mutations were significantly associated with positive ER-(P = 0.016) and PR (P = 0.002) but negative HER2-(P = 0.001) status.…”

Section: Discussionmentioning

confidence: 76%

Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

Xiao¹,

Zhang²,

Chen³

et al. 2021

J. Cancer

View full text Add to dashboard Cite

Background: Comprehensive analysis of PI3K-AKT-mTOR pathway gene alterations in breast cancer may be helpful for targeted therapy. Methods: We performed targeted sequencing using a panel of 520 cancer-related genes to investigate gene alterations in the PI3K-AKT-mTOR pathway from 589 consecutive Chinese women diagnosed with stage I-III breast cancer. Analyses of overall survival (OS) were performed using the publicly available clinical and genomic data from METABRIC. Results: PI3K-AKT-mTOR pathway gene alterations were detected in 62.6% (369/589) of our cohort. The most commonly altered genes were PIK3CA (45%), PTEN (7.5%), AKT1 (5.9 %), PIK3R1 (2.7%), and PIK3CG (2%). Four PIK3CA mutations (E545K, H1047R, E542K, and H1047L) were detected in all the breast cancer molecular subtypes. Seven PIK3CA mutations (E545G, E418_L422delinsV, E726K, E110del, G1049R, G118D, and D350G) were only detected in HR + subtypes. Two PIK3CA mutations (C420R and N345K) were only detected in non-triple-negative subtypes. Most cases with PTEN mutation were HR + /HER2 -subtype (77.3%), followed by triple-negative subtype (18.2%). In the METABRIC breast cancer dataset, no significant OS difference was observed between the PIK3CA-mutant and wild-type groups. However, patients with multiple PIK3CA mutations (mOS: 131 vs. 159 months, P= 0.029), or PIK3CA mutations located in the C2 domain had significantly shorter OS (mOS, 130 vs. 154 months, P=0.020) than those without the mutations. Conclusions: Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of PIK3CA mutations have distinct prognostic impact.

show abstract

Section: Discussionmentioning

confidence: 76%

Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

Xiao¹,

Zhang²,

Chen³

et al. 2021

J. Cancer

View full text Add to dashboard Cite

show abstract

“…We showed that AKT1 E17K-mutated meningiomas have a less immunosuppressive tumour microenvironment when compared to grade I NF2 meningiomas; this may explain why some NF2 tumours have high progression/recurrence rates. The molecular mechanism of how AKT1 E17K or NF2 loss influences immunosuppressive environment in the tumour is likely to involve different cell types and be more complex [39]. However, to our knowledge, this is the first time that differences in M2 macrophages in grade I meningiomas have been linked to driver mutations, and could potentially help in developing directed immunotherapies in genetically stratified meningioma patients.…”

Section: Discussionmentioning

confidence: 94%

A Rapid Robust Method for Subgrouping Non-NF2 Meningiomas According to Genotype and Detection of Lower Levels of M2 Macrophages in AKT1 E17K Mutated Tumours

Adams

Ercolano

Ferluga

et al. 2020

IJMS

View full text Add to dashboard Cite

The majority of meningiomas are grade I, but some grade I tumours are clinically more aggressive. Recent advances in the genetic study of meningiomas has allowed investigation into the influence of genetics on the tumour microenvironment, which is important for tumorigenesis. We have established that the endpoint genotyping method Kompetitive Allele Specific PCR (KASP™) is a fast, reliable method for the screening of meningioma samples into different non-NF2 mutational groups using a standard real-time PCR instrument. This genotyping method and four-colour flow cytometry has enabled us to assess the variability in the largest immune cell infiltrate population, M2 macrophages (CD45+HLA-DR+CD14+CD163+) in 42 meningioma samples, and to suggest that underlying genetics is relevant. Further immunohistochemistry analysis comparing AKT1 E17K mutants to WHO grade I NF2-negative samples showed significantly lower levels of CD163-positive activated M2 macrophages in meningiomas with mutated AKT1 E17K, signifying a more immunosuppressive tumour microenvironment in NF2 meningiomas. Our data suggested that underlying tumour genetics play a part in the development of the immune composition of the tumour microenvironment. Stratifying meningiomas by mutational status and correlating this with their cellular composition will aid in the development of new immunotherapies for patients.

show abstract

“…The results indicated that AKT1, TP53, UBC, PTEN, and CCND1 may be pivotal targets in correlation with melanoma metastasis. Previous studies suggested that AKT1 promoted the development of melanoma metastases (Cho et al, 2015), and its melanoma-derived mutation, AKT1 E17K , activated focal adhesion kinase and promoted melanoma brain metastasis (Kircher et al, 2019). In addition, p53, encoding by TP53 gene, was reported as a therapeutic target of melanoma (Wu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Identification of Metastasis-Associated MicroRNAs in Metastatic Melanoma by miRNA Expression Profile and Experimental Validation

Gao¹,

et al. 2021

Front. Genet.

View full text Add to dashboard Cite

It is reported that microRNAs (miRNA) have paramount functions in many cellular biological processes, development, metabolism, differentiation, survival, proliferation, and apoptosis included, some of which are involved in metastasis of tumors, such as melanoma. Here, three metastasis-associated miRNAs, miR-18a-5p (upregulated), miR-155-5p (downregulated), and miR-93-5p (upregulated), were identified from a total of 63 different expression miRNAs (DEMs) in metastatic melanoma compared with primary melanoma. We predicted 262 target genes of miR-18a-5p, 904 miR-155-5p target genes, and 1220 miR-93-5p target genes. They participated in pathways concerning melanoma, such as TNF signaling pathway, pathways in cancer, FoxO signaling pathway, cell cycle, Hippo signaling pathway, and TGF-beta signaling pathway. We identified the top 10 hub nodes whose degrees were higher for each survival-associated miRNA as hub genes through constructing the PPI network. Using the selected miRNA and the hub genes, we constructed the miRNA-hub gene network, and PTEN and CCND1 were found to be regulated by all three miRNAs. Of note, miR-155-5p was obviously downregulated in metastatic melanoma tissues, and miR-18a-5p and miR-93-5p were obviously regulated positively in metastatic melanoma tissues. In validating experiments, miR-155-5p's overexpression inhibited miR-18a-5p's and miR-93-5p's expression, which could all significantly reduce SK-MEL-28 cells' invasive ability. Finally, miR-93-5p and its potential target gene UBC were selected for further validation. We found that miR-93-5p's inhibition could reduce SK-MEL-28 cell's invasive ability through upregulated the expression of UBC, and the anti-invasive effect was reserved by downregulation of UBC. The results show that the selected three metastasis-associated miRNAs participate in the process of melanoma metastasis via regulating their target genes, providing a potential molecular mechanism for this disease.

show abstract

AKT1E17K Activates Focal Adhesion Kinase and Promotes Melanoma Brain Metastasis

Cited by 49 publications

References 53 publications

Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

A Rapid Robust Method for Subgrouping Non-NF2 Meningiomas According to Genotype and Detection of Lower Levels of M2 Macrophages in AKT1 E17K Mutated Tumours

Identification of Metastasis-Associated MicroRNAs in Metastatic Melanoma by miRNA Expression Profile and Experimental Validation

Contact Info

Product

Resources

About