Heterogeneity and Clonal Evolution of Acquired PARP Inhibitor Resistance in <i>TP53-</i> and <i>BRCA1</i>-Deficient Cells

Abstract Homologous recombination (HR)-deficient cancers are sensitive to poly-ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous (HGSC). However, majority patients will relapse, and acquired PARPi resistance is emerging as a pressing problem. Here we generated seven single-cell clones with derived from PARPi-sensitive TP53−/− BRCA1−/− epithelial cell line using CRISPR/Cas9. These showed diverse mechanisms, some presented multiple mechanisms at same time. Genomic analysis revealed unique transcriptional mutational profiles increased genomic instability comparison line. Clonal evolutionary analyses suggested that arose via clonal selection an intrinsically unstable heterogenous population line, contained preexisting drug-tolerant cells. Similarly, spatial heterogeneity tumor biopsies patient BRCA1-mutant HGSC was observed. In imaging-based drug screening, responses targeted therapeutic agents, indicating not all PARPi-resistant can be just one therapy. Furthermore, mechanism-dependent vulnerabilities selected demonstrating deeper understanding on could lead improved targeting biomarkers for resistance. Significance: This study shows BRCA1-deficient cells give rise genomically functionally clones, associated various mechanism-specific manner.