Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Henneman, Linda; van Miltenburg, Martine H; Michalak, Ewa M; Braumuller, Tanya M; Jaspers, Janneke E; Drenth, Anne Paulien; de Korte-Grimmerink, Renske; Gogola, Ewa; Szuhai, Karoly; Schlicker, Andreas; Bin Ali, Rahmen; Pritchard, Colin; Huijbers, Ivo J; Berns, Anton; Rottenberg, Sven; Jonkers, Jos (2015). Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 112(27), pp. 8409-8414. National Academy of Sciences NAS 10.1073/pnas.1500223112

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Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics.

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