Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan.
There is no tailored therapy yet for human basal-like mammary carcinomas. However, BRCA1 dysfunction is frequently present in these malignancies, compromising homology-directed DNA repair. This defect may serve as the tumor's Achilles heel and make the tumor hypersensitive to DNA breaks. We have evaluated this putative synthetic lethality in a genetically engineered mouse model for BRCA1-associated breast cancer, using the topoisomerase I (Top1) poison topotecan as monotherapy and in combination with poly(ADP-ribose) polymerase inhibition by olaparib. All 20 tumors tested were topotecan sensitive, but response heterogeneity was substantial. Although topotecan increased mouse survival, all tumors eventually acquired resistance. As mechanisms of in vivo resistance, we identified overexpression of Abcg2/Bcrp and markedly reduced protein levels of the drug target Top1 (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 the 11 Abcg2(-/-);Brca1(-/-);p53(-/-) tumors were 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.
Division of Molecular Biology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
Serge A L
SA
Zander
Ariena
A
Kersbergen
Eline
E
van der Burg
Niels
N
de Water
Olaf
O
van Tellingen
Sjöfn
S
Gunnarsdottir
Janneke E
JE
Jaspers
Marina
M
Pajic
Anders O H
AO
Nygren
Jos
J
Jonkers
Piet
P
Borst
Sven
S
Rottenberg
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019398:Genes, BRCA1 / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020714:Maximum Tolerated Dose; D051379:Mice; D018345:Mice, Knockout; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage / Q000627:therapeutic use*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004317:Doxorubicin; C507084:Abcb1b protein, mouse; C531550:olaparib