Cytochrome P450 1B1 (CYP1B1) is mostly expressed in tumours and displays unusual properties. Its two polymorphic forms were differently associated with anticancer drug sensitivity. We decipher here the role of this polymorphism in anticancer drug efficacy in vitro, in vivo and in the clinical setting.
From head-and-neck squamous cell carcinoma cell lines not expressing CYP1B1, we generated isogenic derivatives expressing the two forms. Proliferation, invasiveness, stem cell characteristics, sensitivity to anticancer agents and transcriptome were analysed. Tumour growth and chemosensitivity were studied in vivo. A prospective clinical trial on 121 patients with advanced head-and-neck cancers was conducted, and a validation-retrospective study was conducted.
Cell lines expressing the variant form displayed high rates of in vitro proliferation and invasiveness, stemness features and resistance to DNA-damaging agents. In vivo, tumours expressing the variant CYP1B1 had higher growth rates and were markedly drug-resistant. In the clinical study, overall survival was significantly associated with the genotypes, wild-type patients presenting a longer median survival (13.5 months) than the variant patients (6.3 months) (p = 0.0166).
This frequent CYP1B1 polymorphism is crucial for cancer cell proliferation, migration, resistance to chemotherapy and stemness properties, and strongly influences head-and-neck cancer patients’ survival.
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We are grateful to Dr Laurence Bresson-Bepoldin and Dr Frédéric Delom for their kind support during the preparation of the paper. We are indebted to Prof Jean-Pierre Delord for his implication in the clinical validation study.
Ethics approval and consent to participate
CAL27 and CAL33 HNSCC cell lines were kindly provided by Dr J.L. Fischel (Centre Antoine Lacassagne, Nice, France, where they were initially obtained). They were authenticated by Azur Génétique (Nice, France) as identical to the corresponding DSMZ cell lines (report reference AGLC-14-00225). The study was approved by the local ethical committee (Comité de Protection des Personnes de Bordeaux), and written informed consent was provided by all the participants after a full explanation of the study was given to them. This study was performed in accordance with the Declaration of Helsinki and was registered under ref. NCT-01827956.
Consent to publish
Raw results of the RNA-seq are available on the Annotare platform (ArrayExpress accession #E-MTAB-8512).
The authors declare no competing interests.
This work was made possible through grants from the Ligue Nationale contre le Cancer (comité des Landes) and from GEFLUC-Aquitaine.
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Morvan, V.L., Richard, É., Cadars, M. et al. Cytochrome P450 1B1 polymorphism drives cancer cell stemness and patient outcome in head-and-neck carcinoma. Br J Cancer 123, 772–784 (2020). https://doi.org/10.1038/s41416-020-0932-5