Unravelling therapy resistance in mouse models of human breast cancer


Session type:

Jos Jonkers1
1Netherlands Cancer Institute, Amsterdam, The Netherlands


Mouse models of human cancer not only permit us to gain a detailed insight into the specific genetic changes that drive tumour development and metastasis but also provide powerful 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 elicit recurrent disease.

We have developed genetically engineered mouse models (GEMMs) of E-cadherin mutated lobular breast cancer. These mice develop mammary tumours that closely resemble the lobular morphology and the metastatic spectrum of the cognate tumours in humans. We have used Sleeping Beauty (SB)-based insertional mutagenesis (IM) screens in conditional E-cadherin mutant mice to identify cancer genes that collaborate with E-cadherin loss in mammary tumorigenesis. Approximately 50% of all tumours carry activating SB insertions in Fgfr2. These tumours are highly sensitive to FGFR inhibitors but eventually become resistant due to de novo SB insertions in genes that are causal to the resistance phenotype.

We have also established GEMMs and patient-derived xenograft (PDX) models for BRCA1-deficient triple-negative breast cancer. These mice develop mammary tumours that are characterised by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Nevertheless, none of these drugs are curative: tumours grow back after drug treatment and eventually become resistant. Resistance of BRCA1-deficient GEMM tumours to the PARP inhibitor olaparib can be induced by several mechanisms, including activation of drug efflux transporters, type of BRCA1 mutation and 53BP1 loss. Therapy resistance of BRCA1-methylated PDX tumours is driven by loss of BRCA1 promoter methylation or by a novel resistance mechanism involving de novo BRCA1 gene fusions created by intrachromosomal genomic rearrangements.