A molecular signature of well-differentiated oral squamous cell carcinoma reveals a resistance mechanism to metronomic chemotherapy and novel therapeutic candidates

J Drug Target. 2021 Dec;29(10):1118-1127. doi: 10.1080/1061186X.2021.1929256. Epub 2021 May 27.

Abstract

Well-differentiated head and neck squamous cell carcinoma (HNSCC), accounts for approximately 10% of all HNSCCs and, while these cases are associated with good prognosis after surgery, these are resistant to chemotherapy. Here we designed a retrospective study to evaluate the effects of histological differentiation on tongue squamous cell carcinoma (TSCC) patients undergoing surgery or metronomic neoadjuvant chemotherapy. The metronomic neoadjuvant chemotherapy significantly improved overall survival of patients with poorly or moderately differentiated tumour, but not those with well-differentiated tumour. Analysis of the Cancer Genome Atlas (TCGA) showed that FAT1 mutations were significantly enriched in more differentiated HNSCC while ASPM mutations were significantly enriched among the poorly differentiated HNSCC. Interestingly, Wnt/β-catenin pathway was activated in well-differentiated HNSCC. Active β-catenin is translocated to the nucleus in the well-differentiated oral squamous cell carcinoma cell lines. Wnt inhibitor, Wnt974, were synergistic with methotrexate in killing well-differentiated oral squamous cell carcinoma (OSCC) cell lines. TCGA data analyses reveal a signature in patients with well-differentiated HNSCC who have no benefits from metronomic neoadjuvant chemotherapy, suggesting that there might be novel nosology and therapeutic candidates for improving HNSCC patient survival. Well-differentiated OSCC is synergistically killed by combination chemotherapy with Wnt inhibitor, making it promising therapeutic candidates.

Keywords: Chemotherapy resistance; metronomic chemotherapy; well-differentiation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Metronomic
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • Male
  • Methotrexate / administration & dosage
  • Middle Aged
  • Neoadjuvant Therapy
  • Pyrazines / administration & dosage
  • Pyridines / administration & dosage
  • Retrospective Studies
  • Squamous Cell Carcinoma of Head and Neck / drug therapy*
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Survival Rate
  • Tongue Neoplasms / drug therapy*
  • Tongue Neoplasms / genetics
  • Tongue Neoplasms / pathology
  • Wnt Signaling Pathway / drug effects
  • Young Adult

Substances

  • Pyrazines
  • Pyridines
  • LGK974
  • Methotrexate