Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors

Cancer Lett. 2017 Apr 28:392:71-82. doi: 10.1016/j.canlet.2017.01.024. Epub 2017 Jan 23.

Abstract

The genomic alterations identified in head and neck squamous cell carcinoma (HNSCC) tumors have not resulted in any changes in clinical care, making the development of biomarker-driven targeted therapy for HNSCC a major translational gap in knowledge. To fill this gap, we used 59 molecularly characterized HNSCC cell lines and found that mutations of AJUBA, SMAD4 and RAS predicted sensitivity and resistance to treatment with inhibitors of polo-like kinase 1 (PLK1), checkpoint kinases 1 and 2, and WEE1. Inhibition or knockdown of PLK1 led to cell-cycle arrest at the G2/M transition and apoptosis in sensitive cell lines and decreased tumor growth in an orthotopic AJUBA-mutant HNSCC mouse model. AJUBA protein expression was undetectable in most AJUBA-mutant HNSCC cell lines, and total PLK1 and Bora protein expression were decreased. Exogenous expression of wild-type AJUBA in an AJUBA-mutant cell line partially rescued the phenotype of PLK1 inhibitor-induced apoptosis and decreased PLK1 substrate inhibition, suggesting a threshold effect in which higher drug doses are required to affect PLK1 substrate inhibition. PLK1 inhibition was an effective therapy for HNSCC in vitro and in vivo. However, biomarkers to guide such therapy are lacking. We identified AJUBA, SMAD4 and RAS mutations as potential candidate biomarkers of response of HNSCC to treatment with these mitotic inhibitors.

Keywords: AJUBA; CHK1; Head neck squamous cell carcinoma; Polo-like kinase 1; WEE1.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Checkpoint Kinase 1 / antagonists & inhibitors
  • Checkpoint Kinase 1 / metabolism
  • Checkpoint Kinase 2 / antagonists & inhibitors
  • Checkpoint Kinase 2 / metabolism
  • Dose-Response Relationship, Drug
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Genotype
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / enzymology
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • LIM Domain Proteins / genetics*
  • Mice, Nude
  • Molecular Targeted Therapy
  • Mutation*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Phenotype
  • Polo-Like Kinase 1
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Pteridines / pharmacology*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Pyrimidinones
  • RNA Interference
  • Signal Transduction / drug effects
  • Smad4 Protein / genetics
  • Squamous Cell Carcinoma of Head and Neck
  • Thiophenes / pharmacology
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Urea / analogs & derivatives
  • Urea / pharmacology
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics

Substances

  • 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
  • AJUBA protein, human
  • Antineoplastic Agents
  • BI 6727
  • Cell Cycle Proteins
  • LIM Domain Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pteridines
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • SMAD4 protein, human
  • Smad4 Protein
  • Thiophenes
  • bora protein, human
  • Urea
  • Checkpoint Kinase 2
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Protein Serine-Threonine Kinases
  • ras Proteins
  • adavosertib