Paclitaxel Resistance Increases Oncolytic Adenovirus Efficacy Via Upregulated CAR Expression and Dysfunctional Cell Cycle Control

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2015 Jan 7

PMID 25560085

Citations 21

Authors

Carin K Ingemarsdotter

Laura A Tookman

Ashley Browne

Katrina Pirlo

Rosalind Cutts

Claude Chelela

Karisma F Khurrum

Elaine Y L Leung

Suzanne Dowson

Lee Webber

Iftekhar Khan

Darren Ennis

Nelofer Syed

Tim R Crook

James D Brenton

Michelle Lockley

Iain A McNeish

Affiliations

Soon will be listed here.

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.

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