Abstract IA9: Studying therapy response and resistance in mouse models of human breast cancer

Abstract

Abstract Mouse models of human cancer not only permit us to gain a detailed insight into the specific genetic changes that drive tumor 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 might elicit recurrent disease. We have developed genetically engineered mouse models (GEMMs) of E-cadherin mutated lobular breast cancer. These mice develop mammary tumors that closely resemble the lobular morphology and the metastatic spectrum of the cognate tumors 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 tumors carry activating SB insertions in Fgfr2. These tumors are highly sensitive to FGFR inhibitors but eventually become resistant. We are currently analyzing SB insertions in FGFRi-resistant tumors to identify 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 tumors that are characterized by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Nevertheless, none of these drugs are curative: tumors grow back after drug treatment and eventually become resistant. We have used DNA methylation analysis and focused or whole-exome sequencing to identify resistance mechanisms in matched pairs of therapy-sensitive and –resistant BRCA1-deficient mammary tumors from our GEMMs and PDX models. We found that resistance of BRCA1-deficient GEMM tumors to the PARP inhibitor olaparib can be induced by several mechanisms, including activation of P-glycoprotein drug efflux transporters, type of BRCA1 founder mutation and 53BP1 loss. Therapy resistance of BRCA1-mutated PDX tumors is caused by additional intragenic deletions that lead to restoration of the open reading frame. Therapy resistance of BRCA1-methylated PDX tumors 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. Citation Format: Jos Jonkers. Studying therapy response and resistance in mouse models of human breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA9.