Studying cancer drug resistance using BRCA-deficient mouse mammary tumor organoids

Poly\(ADP-ribose) polymerase inhibition \(PARPi) is a promising new therapeutic approach for the treatment of cancers that show homologous recombination de ciency \(HRD).Despite the success of PARPi in targeting HRD in tumors that lack BRCA1 or BRCA2 function, drug resistance poses a major obstacle to PARPi e cacy.Several resistance mechanisms have been identi ed in cultured cells, but testing their relevance for in vivo resistance is cumbersome.As a novel approach to investigate these, we describe here the use of 3D cancer organoids derived from genetically engineered mouse models \ (GEMMs) for BRCA1/2-de cient cancers.Unlike conventional cell lines or mammospheres, organoid cultures can be e ciently derived and rapidly expanded in vitro.Orthotopically transplanted organoids give rise to mammary tumors that recapitulate the epithelial morphology and preserve the drug response of the original tumor.Importantly, GEMM tumor-derived organoids can be easily genetically modi ed providing a powerful tool for genetic studies.