EZN-2208 (PEG-SN38) overcomes ABCG2-mediated topotecan resistance in BRCA1-deficient mouse mammary tumors
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Serge A L Zander1, Wendy Sol, Lee Greenberger
1Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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;Brca1(F/F);p53(F/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.
Insights
Pegylated topoisomerase I inhibitors like EZN-2208 show promise in overcoming drug resistance in BRCA1-mutated breast cancers. This novel approach offers more durable responses than traditional therapies by circumventing ABCG2 transporter overexpression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- BRCA1 dysfunction in hereditary breast cancer impairs DNA repair, leading to sensitivity to topoisomerase I inhibitors.
- Resistance to topotecan and irinotecan often develops due to ABCG2 transporter overexpression in BRCA1-deficient tumors.
Purpose of the Study:
- To evaluate the efficacy of the pegylated SN38 compound EZN-2208 against BRCA1-mutated tumors exhibiting ABCG2-mediated resistance.
- To assess the potential of combining ABCG2 inhibition with topoisomerase I inhibitors.
Main Methods:
- Utilized a conditional K14cre;Brca1(F/F);p53(F/F) mouse model with BRCA1-deficient mammary tumors.
- Tested EZN-2208, topotecan, and irinotecan therapies in these models.
- Investigated the effect of ABCG2 inhibition using Ko143 in relevant tumor models.
Main Results:
- EZN-2208 demonstrated more pronounced and durable responses in ABCG2-positive tumors compared to topotecan or irinotecan.
- Co-administration of Ko143 with topotecan showed a moderate increase in survival but did not match EZN-2208's efficacy.
- EZN-2208 effectively circumvents ABCG2-mediated drug efflux.
Conclusions:
- Pegylation of topoisomerase I inhibitors is a viable strategy to overcome efflux transporter-mediated resistance.
- EZN-2208 shows potential for improved therapeutic efficacy in BRCA1-mutated cancers resistant to conventional treatments.
