Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Department of Biomedical System Informatics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
Cell Rep. 2023 May 30;42(5):112538. doi: 10.1016/j.celrep.2023.112538. Epub 2023 May 19.
BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.
BRCA1 和 BRCA2 都通过同源重组（HR）在 DNA 双链断裂修复中发挥作用。由于其 HR 缺陷，BRCA1/2 缺陷型癌症对聚（ADP-核糖）聚合酶抑制剂（PARPis）敏感，但最终会产生耐药性。临床前研究产生了几种不涉及 BRCA1/2 再激活的 PARPi 耐药机制，但它们在临床上的相关性仍不清楚。为了研究哪些 BRCA1/2 独立的机制在体内驱动自发耐药，我们将分子谱分析与 PARPi 初治和 PARPi 耐药的具有大基因内缺失的小鼠乳腺肿瘤的 HR 功能分析相结合，这些缺失阻止了 BRCA1/2 的再激活。我们观察到 62%的 PARPi 耐药 BRCA1 缺陷型肿瘤中 HR 得到恢复，但在 PARPi 耐药 BRCA2 缺陷型肿瘤中则没有。此外，我们发现 53BP1 缺失是 HR 功能正常的 BRCA1 缺陷型肿瘤中普遍的耐药机制，而 BRCA2 缺陷型肿瘤中的耐药性主要是由 PARG 缺失诱导的。此外，联合多组学分析确定了其他潜在参与调节 PARPi 反应的基因和途径。
