Abstract

Mouse models of human cancer provide powerful in vivo tools to study the mechanisms underlying drug response and acquired resistance. Once these processes are understood in sufficient detail it may be possible to design (combination) therapies that not only cause complete remissions but also eliminate remnant cells that may elicit recurrent disease.

We have established genetically engineered mouse models (GEMMs) and human breast cancer xenograft models for BRCA-deficient breast cancer. These mice develop mammary tumors that are characterised by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. We have used these mammary tumor models for preclinical evaluation of therapy response and elucidation of mechanisms of acquired drug resistance. BRCA-deficient mammary tumors are highly sensitive to PARP inhibitors and platinum drugs, but none of these drugs is capable of causing tumor eradication: tumors grow back after drug treatment and eventually become resistant. Using in vitro functional genetic screens, in vivo genotype-phenotype correlation studies and genomic analysis of therapy-resistant tumors, we found that therapy response and resistance to platinum drugs and the clinical PARP inhibitor olaparib is affected by several factors, including drug efflux transporter activity, the type of BRCA1 founder mutation and 53BP1 status.