In this study, we combined functional analysis of HR status with multi-omics analysis of a collection of matched PARPi-naive and PARPi-resistant BRCA1-knockout (KO) and BRCA2-KO mouse mammary tumors to classify the contribution of previously reported non-reversion resistance mechanisms in a preclinical “in vivo reality” of spontaneously acquired resistance. The gene discussed is BRCA1; the disease is breast cancer.