Abstract 2200: Relationship between cytochrome P450 1B1 (CYP1B1) and head and neck cancer cells proliferation, dissemination and chemosensitivity to anticancer drugs

Contrasting to other cytochromes P450, CYP1B1 is essentially present in tumour tissue and has been suspected to play a role in oncogenesis and drug resistance. We have recently shown that a CYP1B1 single nucleotide gene polymorphism (rs1056836, 1697 G>C, V432L) was significantly associated with the cytotoxicity of DNA-damaging anticancer drugs in two independent panels of tumour cell lines, the NCI-60 panel and the JFCR-45 panel. In order to identify the molecular mechanisms involved in the role of CYP1B1 polymorphism in anticancer drug resistance, we selected head-and-neck cancer cell lines with no basal expression of CYP1B1 due to promoter hypermethylation and generated by lentiviral infection isogenic variants differing only by this single nucleotide in the CYP1B1 gene. Cell proliferation was strongly enhanced in cells re-expressing CYP1B1 and further increased in cells harbouring the C/C genotype (C/C cells) as compared to those harbouring the G/G genotype (G/G cells). The cytotoxicity of a panel of anticancer drugs from all drug classes was evaluated on these established cell lines. Significantly higher IC50s of most of them (excepted oxaliplatin and gemcitabine) were noticed for C/C cells as compared to G/G cells in agreement with what was observed in the NCI and JFCR panels. Migration capacity of these cell lines was studied using the scratch wound assay and proteins involved in cell adhesion were evaluated by Western blotting. Cells re-expressing CYP1B1 were able to migrate significantly more rapidly than original cells and this was further enhanced in C/C cells as compared to G/G cells. E-cadherin expression was decreased in C/C cells while vimentin expression was increased in G/G cells. The clinical consequences of the CYP1B1 L432V gene polymorphism were studied in a prospective population of 123 head-and-neck cancer patients treated by chemotherapy associated with cetuximab in the palliative setting, either with locally advanced or with metastatic disease. There were 48 C/C patients, 40 heterozygotes C/G and 35 G/G patients, giving an allele frequency of 45%. No differences in progression rates as a function of the polymorphism were noticed. Overall median survival (OMS) was significantly worse in C/C patients (6.6 months) than in G/G patients (13.2 months), heterozygotes falling in between (9.8 months) (p = 0.017). Taking into account only the metastatic patients (47 patients) revealed more profound differences between C/C patients (OMS = 3.8 m