EZN-2208 (PEG-SN38) Overcomes ABCG2-Mediated Topotecan Resistance in BRCA1-Deficient Mouse Mammary Tumors

Serge A L Zander,Lee Greenberger,Yixian Zhang,Olaf Van Tellingen,Sven Rottenberg,Piet Borst,Jos Jonkers,Wendy Sol,Jian-Ting Zhang

doi:10.1371/journal.pone.0045248

Abstract

BRCA1 dysfunction in hereditary breast cancer causes defective homology-directed DNA repair and sensitivity towards DNA damaging agents like the clinically used topoisomerase I inhibitors topotecan and irinotecan. Using our conditional K14cre;Brca1F/F;p53F/F mouse model, we showed previously that BRCA1;p53-deficient mammary tumors initially respond to topotecan, but frequently acquire resistance by overexpression of the efflux transporter ABCG2. Here, we tested the pegylated SN38 compound EZN-2208 as a novel approach to treat BRCA1-mutated tumors that express ABCG2. We found that EZN-2208 therapy resulted in more pronounced and durable responses of ABCG2-positive tumors than topotecan or irinotecan therapy. We also evaluated tumor-specific ABCG2 inhibition by Ko143 in Abcg2−/− host animals that carried tumors with topotecan-induced ABCG2 expression. Addition of Ko143 moderately increased overall survival of these animals, but did not yield tumor responses like those seen after EZN-2208 therapy. Our results suggest that pegylation of Top1 inhibitors may be a useful strategy to circumvent efflux transporter-mediated resistance and to improve their efficacy in the clinic.

Highlights

Poisoning topoisomerase I (Top1) is a useful therapeutic approach to target cancer cells with intrinsic defects in the DNA damage response [1]
When tumors reached a volume of 150–250 mm3 after transplantation, animals were either left untreated or injected with topotecan until the tumor volume doubled to about 400 mm3 (Fig. 1A)
There was a clear induction of ABCG2 in the topotecan-resistant tumors in the donor tumors used for this study (Fig. 2 and Table S2)

Summary

Introduction

Poisoning topoisomerase I (Top1) is a useful therapeutic approach to target cancer cells with intrinsic defects in the DNA damage response [1]. In particular the camptothecin derivatives topotecan and irinotecan are frequently used to target Top in ovarian, colon, and small cell lung cancer patients. Both topotecan and SN38, the active metabolite of irinotecan, stabilize Top1-DNA cleavage complexes (Top1cc), which are subsequently converted into DNA damage during DNA replication and transcription. Defects of tumor cells in proper repair of DSB provide an Achilles heel that can be targeted using Top inhibitors. An example is the increased topotecan sensitivity of cultured cells that are deficient in BRCA1 function [3], which is critical for error-free repair of DSB by homologous recombination (HR) [4]

Methods

Results

Conclusion