title: Paclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control.
abstract: Resistance to paclitaxel chemotherapy frequently develops in ovarian cancer. Oncolytic adenoviruses are a novel therapy for human malignancies that are being evaluated in early phase trials. However, there are no reliable predictive biomarkers for oncolytic adenovirus activity in ovarian cancer. We investigated the link between paclitaxel resistance and oncolytic adenovirus activity using established ovarian cancer cell line models, xenografts with de novo paclitaxel resistance and tumour samples from two separate trials. The activity of multiple Ad5 vectors, including dl922-947 (E1A CR2-deleted), dl1520 (E1B-55K deleted) and Ad5 WT, was significantly increased in paclitaxel resistant ovarian cancer in vitro and in vivo. This was associated with greater infectivity resulting from increased expression of the primary receptor for Ad5, CAR (coxsackie adenovirus receptor). This, in turn, resulted from increased CAR transcription secondary to histone modification in resistant cells. There was increased CAR expression in intraperitoneal tumours with de novo paclitaxel resistance and in tumours from patients with clinical resistance to paclitaxel. Increased CAR expression did not cause paclitaxel resistance, but did increase inflammatory cytokine expression. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer. Ad11 and Ad35, both group B adenoviruses that utilise non-CAR receptors to infect cells, are also significantly more effective in paclitaxel-resistant ovarian cell models. Inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms - if validated further, this information could have future clinical utility to aid patient selection for clinical trials.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Carin K
authors.initials: CK
authors.lastname: Ingemarsdotter
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Tookman
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Browne
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: Pirlo
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Cutts
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Claude
authors.initials: C
authors.lastname: Chelela
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Karisma F
authors.initials: KF
authors.lastname: Khurrum
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Elaine Y L
authors.initials: EY
authors.lastname: Leung
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Dowson
authors.affiliation: Cancer Research UK and UCL Clinical Trials Centre, London, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Webber
authors.affiliation: Cancer Research UK and UCL Clinical Trials Centre, London, UK.
authors.forename: Iftekhar
authors.initials: I
authors.lastname: Khan
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Ennis
authors.affiliation: Division of Brain Sciences, Faculty of Medicine, Imperial College, London, UK.
authors.forename: Nelofer
authors.initials: N
authors.lastname: Syed
authors.affiliation: Dundee Cancer Centre, University of Dundee, Ninewells Hospital, Dundee, UK.
authors.forename: Tim R
authors.initials: TR
authors.lastname: Crook
authors.affiliation: Cancer Research UK Cambridge Institute, Cambridge, UK.
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lockley
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. Electronic address: iain.mcneish@glasgow.ac.uk.
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008819:Mice, Nude; D050504:Oncolytic Viruses / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016207:Cytokines; D006657:Histones; D018836:Inflammation Mediators; D012333:RNA, Messenger; D017239:Paclitaxel
keywords: Adenovirus; Cell cycle control; Coxsackie adenovirus receptor; Ovarian cancer; Paclitaxel resistance