Open AccessPaclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control
Author(s) -
Ingemarsdotter Carin K.,
Tookman Laura A.,
Browne Ashley,
Pirlo Katrina,
Cutts Rosalind,
Chelela Claude,
Khurrum Karisma F.,
Leung Elaine Y.L.,
Dowson Suzanne,
Webber Lee,
Khan Iftekhar,
Ennis Darren,
Syed Nelofer,
Crook Tim R.,
Brenton James D.,
Lockley Michelle,
McNeish Iain A.
Publication year - 2015
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2014.12.007
Subject(s) - paclitaxel , oncolytic virus , oncolytic adenovirus , ovarian cancer , cancer research , biology , adenoviridae , cancer , medicine , genetic enhancement , biochemistry , tumor cells , gene
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.