Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma.

Authors

Ha Linh Vu, Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
A E Aplin, Department of Cancer Biology, Kimmel Cancer Center, Dermatology and Cutaneous Biology, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

10-1-2014

Comments

This article has been peer reviewed. It was published in: Molecular Cancer Research.

Volume 12, Issue 10, 1 October 2014, Pages 1509-1519.

The published version is available http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482471/

Copyright © 2014 American Association for Cancer Research

Abstract

UNLABELLED: Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to 20% of patients with melanoma have an activating mutation in the GTPase, NRAS. The major downstream effectors of RAS are RAFs (ARAF, BRAF, and CRAF), phosphoinositide 3-kinase (PI3K), and the Ral guanine exchange factors (RalGEF). TANK-binding kinase 1 (TBK1) is an atypical IκB kinase family member that acts downstream of RalGEFs. Whereas many studies have analyzed RAF and PI3K signaling in mutant NRAS melanoma, the role of RalGEF/Ral is understudied and TBK1 has not been examined. To address this, TBK1 was modulated with knockdown approaches and targeted therapies to determine the role of TBK1 in motility, apoptosis, and signaling. In melanoma, NRAS overexpression increased TBK1 phosphorylation. TBK1 depletion inhibited migration and invasion, whereas its constitutive overexpression led to an increase in invasion. In three-dimensional systems that mimic the dermal microenvironment, TBK1 depletion or inhibition cooperated with MEK inhibitors to promote apoptosis, particularly in the context of MEK-insensitive mutant NRAS. This effect was absent in melanoma cells that are wild-type for NRAS. These results suggest the utility of TBK1 inhibitors as part of a treatment regimen for patients with mutant NRAS melanoma, for whom there are no current effective therapies.

IMPLICATIONS: TBK1 promotes the malignant properties of NRAS-mutant melanoma and its targeting, in combination with MEK, promotes apoptosis, thus providing a potential novel targeted therapeutic option.

Recommended Citation

Vu, Ha Linh and Aplin, A E, "Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma." (2014). Department of Cancer Biology Faculty Papers. Paper 81.
https://jdc.jefferson.edu/cbfp/81

PubMed ID

24962318