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

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

Acknowledgements

We thank the Laboratory for Analytical Instruments, Education and Research Support Center, Gunma University Graduate School of Medicine.

Author contributions

1. SK conceived and supervised the study. SK was the Principal Investigator and handled all correspondence with the ethics committee.

2. RK-I analysed transcriptomics.

3. TK investigated the histological differentiation of patients.

4. SK, AA, HS, and SM were responsible for data collection from medical records.

5. SK, RK-I, and TK analysed the data and wrote the manuscript. All authors approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets used and/or analysed during the present study are available from the corresponding author upon a reasonable request.

Additional information

Funding

This work was supported by the JSPS KAKENHI (17K15038).