Abstract

Advancing cancer medicine through development of individualized cancer treatment requires detailed knowledge of the mechanisms underlying therapy response and acquired resistance. Mouse models of human cancer provide powerful tools to study these aspects in a realistic in vivo setting.

We have established several genetically engineered mouse models (GEMMs) and patient-derived tumor xenograft (PDX) models for BRCA1-deficient breast cancer. These mice develop mammary tumors that are characterized 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. Using functional genetic screens, reverse genetics and genomic analysis of therapy-resistant tumors, we found that therapy response and resistance of BRCA1-deficient mammary tumors to cisplatin and the clinical PARP inhibitor olaparib is affected by several factors, including drug efflux transporter activity, type of BRCA1 founder mutation and 53BP1 or REV7 status. Also BRCA1 re-activation via genetic or epigenetic mechanisms contributes to acquired therapy resistance in PDX models of BRCA1-deficient breast cancer.