AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis

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

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

AKT1^E17K activates focal adhesion kinase and promotes melanoma brain metastasis

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

Melanoma Medical Oncology

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1^E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1^E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1^E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets.

Original language	English (US)
Pages (from-to)	1787-1800
Number of pages	14
Journal	Molecular Cancer Research
Volume	17
Issue number	9
DOIs	https://doi.org/10.1158/1541-7786.MCR-18-1372
State	Published - 2019

ASJC Scopus subject areas

Molecular Biology
Oncology
Cancer Research

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Functional Proteomics Reverse Phase Protein Array Core

Access to Document

10.1158/1541-7786.MCR-18-1372

Cite this

Kircher, D. A., Trombetti, K. A., Silvis, M. R., Parkman, G. L., Fischer, G. M., Angel, S. N., Stehn, C. M., Strain, S. C., Grossmann, A. H., Duffy, K. L., Boucher, K. M., McMahon, M., Davies, M. A., Mendoza, M. C., VanBrocklin, M. W., & Holmen, S. L. (2019). AKT1^E17K activates focal adhesion kinase and promotes melanoma brain metastasis. Molecular Cancer Research, 17(9), 1787-1800. https://doi.org/10.1158/1541-7786.MCR-18-1372

Kircher, DA, Trombetti, KA, Silvis, MR, Parkman, GL, Fischer, GM, Angel, SN, Stehn, CM, Strain, SC, Grossmann, AH, Duffy, KL, Boucher, KM, McMahon, M, Davies, MA, Mendoza, MC, VanBrocklin, MW & Holmen, SL 2019, 'AKT1^E17K activates focal adhesion kinase and promotes melanoma brain metastasis', Molecular Cancer Research, vol. 17, no. 9, pp. 1787-1800. https://doi.org/10.1158/1541-7786.MCR-18-1372

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title = "AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis",

abstract = "Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets.",

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

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T1 - AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis

AU - Kircher, David A.

AU - Trombetti, Kirby A.

AU - Silvis, Mark R.

AU - Parkman, Gennie L.

AU - Fischer, Grant M.

AU - Angel, Stephanie N.

AU - Stehn, Christopher M.

AU - Strain, Sean C.

AU - Grossmann, Allie H.

AU - Duffy, Keith L.

AU - Boucher, Kenneth M.

AU - McMahon, Martin

AU - Davies, Michael A.

AU - Mendoza, Michelle C.

AU - VanBrocklin, Matthew W.

AU - Holmen, Sheri L.

PY - 2019

Y1 - 2019

N2 - Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets.

AB - Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets.

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