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.

RAD51 and BRCA2 enhance oncolytic adenovirus type 5 activity in ovarian cancer

“…However, following iso-infection with dl922-947, there were significantly greater increases in both γH2AX positivity and >4N DNA in PEO4 ( Fig. 2A), consistent with our previous observations that virus-induced DNA damage correlates with sensitivity (22,30).…”

“…We have recently shown that oncolytic adenoviruses may be more effective in ovarian cancers with paclitaxel resistance (30). Data here show that these viruses may also have specific activity in another group of poor prognosis ovarian cancers, namely those with platinum and PARP inhibitor resistance thought intact HR function.…”

MiR-125a promotes paclitaxel sensitivity in cervical cancer through altering STAT3 expression

“…4, 5 However, the therapeutic efficacy of paclitaxel is limited, with response rates between 29–63% because of chemoresistance. 4, 5, 6 Paclitaxel resistance is caused by several mechanisms, including overexpression of P-glycoprotein or other drug efflux pumps, 7, 8 alterations to microtubules involved in drug-binding or altered expression of tubulin isotypes and microtubule-associated proteins, 9, 10, 11 alterations to cell cycle and cell survival pathways 12, 13, 14 and the induction of treatment-related autophagy. 15, 16, 17 However, the molecular mechanisms by which resistance to paclitaxel occurs are not fully understood and further investigation is required.…”

A quantitative FastFUCCI assay defines cell cycle dynamics at a single-cell level

“…We demonstrated this possibility with the synergistic interaction between paclitaxel and roscovitine as well as PHA767491, two compounds known to affect DNA replication origins. Other smallmolecule inhibitors with overlapping mechanisms, namely CINK4, flavopiridol, PD-0332991 and purvalanol, have previously been shown to enhance taxane cytotoxicity or reverse taxane resistance (Zhang et al, 2013;Ingemarsdotter et al, 2015;Bible and Kaufmann, 1997;O'Connor et al, 2002). As such a co-targeting strategy is schedule dependent in most cases, the challenge would be to identify optimum dosing regimens that could yield maximal efficacy and minimal toxicity (Jackson et al, 2007;Shah and Schwartz, 2001).…”