Chapter 1 Sensitivity and acquired resistance

identified overexpression of Abcg2/Bcrp and markedly reduced protein levels of the drug target Top 1 (without altered mRNA levels). Tumor-specific genetic ablation of Abcg2 significantly increased overall survival of topotecan-treated animals (P<0.001), confirming the in vivo relevance of ABCG2 for topotecan resistance in a novel approach. Despite the lack of ABCG2, a putative tumor-initiating cell marker, none of 11 Abcg2-/-;Brca1-/-;p53-/- tumors was eradicated, not even by the combination topotecan-olaparib. We find that olaparib substantially increases topotecan toxicity in this model and we suggest that this might also happen in humans. Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan 31 IntroductionTopotecan is used to treat ovarian, cervical and small cell lung cancer patients. Topotecan inhibits topoisomerase I (Top1)-mediated religation of single-stranded DNA breaks (SSBs). When drug-stabilized covalent Top1-DNA complexes cause stalling of the replication machinery, SSBs are converted into double-stranded DN