title: Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Ha Linh
authors: HL
authors: Vu
authors: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Andrew.Aplin@Jefferson.edu.
authors: Andrew E
authors: AE
authors: Aplin
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C517975:AZD 6244; C579675:BX795; D001562:Benzimidazoles; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human