Cisplatin overcomes radiotherapy resistance in OCT4-expressing head and neck squamous cell carcinoma

Johannes Routila; Xi Qiao; Jere Weltner; Juha K Rantala; Timo Carpén; Jaana Hagström; Antti Mäkitie; Ilmo Leivo; Miia Ruuskanen; Jenni Söderlund; Marjut Rintala; Sakari Hietanen; Heikki Irjala; Heikki Minn; Jukka Westermarck; Sami Ventelä

doi:10.1016/j.oraloncology.2022.105772

Cisplatin overcomes radiotherapy resistance in OCT4-expressing head and neck squamous cell carcinoma

Oral Oncol. 2022 Apr:127:105772. doi: 10.1016/j.oraloncology.2022.105772. Epub 2022 Mar 1.

Authors

Johannes Routila¹, Xi Qiao², Jere Weltner³, Juha K Rantala⁴, Timo Carpén⁵, Jaana Hagström⁶, Antti Mäkitie⁵, Ilmo Leivo⁷, Miia Ruuskanen⁸, Jenni Söderlund⁹, Marjut Rintala⁹, Sakari Hietanen¹⁰, Heikki Irjala⁸, Heikki Minn¹¹, Jukka Westermarck¹², Sami Ventelä¹³

Affiliations

¹ Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland.
² Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
³ Department of Clinical Science, Intervention and Technology, Karolinska Institutet, SE-14186 Stockholm, Sweden and Division of Obstetrics and Gynecology, Karolinska Universitetssjukhuset, SE-14186 Stockholm, Sweden.
⁴ MISVIK Biology Ltd, Karjakatu 35 B, 20520 Turku, Finland.
⁵ Department for Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland.
⁶ Department of Oral Pathology and Radiology, University of Turku, Turku, Finland.
⁷ Department of Oral Pathology and Radiology, University of Turku, Turku, Finland; Institute of Biomedicine, Pathology, University of Turku, Kiinamyllynkatu 10 D, 20520 Turku, Finland.
⁸ Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland.
⁹ Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland.
¹⁰ Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku, Finland.
¹¹ FICAN West Cancer Centre, Turku, Finland; Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Turku, Finland.
¹² Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Biomedical Institute, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; FICAN West Cancer Centre, Turku, Finland.
¹³ Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland; FICAN West Cancer Centre, Turku, Finland. Electronic address: satuve@utu.fi.

PMID: 35245886
DOI: 10.1016/j.oraloncology.2022.105772

Abstract

Objectives: Cisplatin is combined with radiotherapy for advanced head and neck squamous cell carcinoma (HNSCC). While providing a beneficial effect on survival, it also causes side effects and thus is an important target when considering treatment de-escalation. Currently, there are no biomarkers to predict its patient-selective therapeutic utility. In this study, we examined the role of the stem cell factor OCT4 as a potential biomarker to help clinicians stratify HNSCC patients between radiotherapy and chemoradiotherapy.

Materials and methods: OCT4 immunohistochemical staining of a population-validated tissue microarray (PV-TMA) (n = 166) representative of a standard HNSCC patients was carried out, and 5-year survival was analyzed. The results were validated using ex vivo drug sensitivity analysis of HNSCC tumor samples, and further cross-validated in independent oropharyngeal (n = 118), nasopharyngeal (n = 170), and vulvar carcinoma (n = 95) clinical datasets. In vitro, genetically modified, patient-derived HNSCC cells were used.

Results: OCT4 expression in HNSCC tumors was associated with radioresistance. However, combination therapy with cisplatin was found to overcome thisradioresistance in OCT4-expressing HNSCC tumors. The results were validated by using several independent patient cohorts. Furthermore, CRISPRa-based OCT4 overexpression in the HNSCC cell line resulted in apoptosis resistance, and cisplatin was found to downregulate OCT4 protein expression in vitro. Ex vivo drug sensitivity analysis of HNSCC tumors confirmed the association between OCT4 expression and cisplatin sensitivity.

Conclusion: This study introduces OCT4 immunohistochemistry as a simple and cost-effective diagnostic approach for clinical practice to identify HNSCC patients benefitting from radiosensitization by cisplatin using either full or reduced dosing.

Keywords: Cisplatin; HNSCC; Head and Neck cancer; OCT4; Radioresistance; Tissue microarray.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Squamous Cell* / drug therapy
Carcinoma, Squamous Cell* / genetics
Carcinoma, Squamous Cell* / radiotherapy
Cell Line, Tumor
Cisplatin / pharmacology
Cisplatin / therapeutic use
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / radiotherapy
Humans
Squamous Cell Carcinoma of Head and Neck / drug therapy
Squamous Cell Carcinoma of Head and Neck / radiotherapy

Substances

Cisplatin