Ghosh Mithun, Kang Min Sil, Katuwal Nar Bahadur, Hong Sa Deok, Park Seong Min, Kim Seul-Gi, Lee Seung Ryeol, Moon Yong Wha
Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si, 13488, Republic of Korea.
Department of Internal Medicine, Hematology and Oncology, CHA Bundang Medical Center, CHA University, Seongnam-si, 13496, Republic of Korea.
Cell Death Dis. 2025 Apr 24;16(1):333. doi: 10.1038/s41419-025-07660-7.
Poly (ADP-ribose) polymerase (PARP) inhibitors are effective in cells with homologous recombination (HR) deficiency, including BRCA1/2 mutation. However, PARP inhibitors remain a therapeutic challenge in breast and ovarian cancer due to inevitably acquired resistance in most cases. Therefore, strategies to overcome PARP inhibitor resistance are unmet clinical need. SRY-box transcription factor 5 (SOX5) plays a crucial role in development of various cancers but the role of SOX5 in PARP inhibitor resistance is poorly understood. This study identified SOX5 as a potential biomarker associated with PARP inhibitor resistance and addressed potential treatment strategies to overcome PARP inhibitor resistance using the olaparib-resistant preclinical model. We observed that SOX5 was significantly upregulated in olaparib-resistant cells and contributed to PARP inhibitor resistance by upregulating DNA repair pathway genes. Ectopic SOX5 overexpression contributed to PARP inhibitor resistance by suppressing DNA double-strand breaks (DSBs) in BRCA-mutated breast and ovarian cancer. SOX5 small interfering RNA combined with olaparib sensitized olaparib-resistant cells and suppressed the growth of olaparib-resistant xenografts in mice via increased DSBs represented by ɣH2AX formation. Mechanistically, SOX5 directly interacted with yes-associated protein 1 (YAP1) and promoted its nuclear translocation by suppressing the Hippo pathway. YAP1, in association with TEA domain family members (TEAD), upregulated HR-related gene expression and conferred PARP inhibitor resistance. Furthermore, the clinical relevance of SOX5 as a therapeutic target was supported by a significant association between SOX5 overexpression and poor prognosis in ovarian cancer on public mRNA microarray data sets. Therefore, we propose SOX5 as a promising therapeutic target for overcoming PARP inhibitor resistance in BRCA1/2-mutated breast and ovarian cancer.
聚（ADP - 核糖）聚合酶（PARP）抑制剂对包括BRCA1/2突变在内的同源重组（HR）缺陷细胞有效。然而，由于在大多数情况下不可避免地会产生耐药性，PARP抑制剂在乳腺癌和卵巢癌的治疗中仍然是一项挑战。因此，克服PARP抑制剂耐药性的策略是尚未满足的临床需求。SRY盒转录因子5（SOX5）在多种癌症的发展中起关键作用，但SOX5在PARP抑制剂耐药性中的作用却知之甚少。本研究确定SOX5为与PARP抑制剂耐药性相关的潜在生物标志物，并使用奥拉帕利耐药的临床前模型探讨了克服PARP抑制剂耐药性的潜在治疗策略。我们观察到SOX5在奥拉帕利耐药细胞中显著上调，并通过上调DNA修复途径基因导致PARP抑制剂耐药。异位SOX5过表达通过抑制BRCA突变的乳腺癌和卵巢癌中的DNA双链断裂（DSB）导致PARP抑制剂耐药。SOX5小干扰RNA与奥拉帕利联合使用可使奥拉帕利耐药细胞敏感，并通过增加以ɣH2AX形成为代表的DSB来抑制奥拉帕利耐药异种移植瘤在小鼠体内的生长。机制上，SOX5直接与Yes相关蛋白1（YAP1）相互作用，并通过抑制Hippo通路促进其核转位。YAP1与TEA结构域家族成员（TEAD）结合，上调HR相关基因表达并赋予PARP抑制剂耐药性。此外，公共mRNA微阵列数据集显示SOX5过表达与卵巢癌预后不良之间存在显著关联，这支持了SOX5作为治疗靶点的临床相关性。因此，我们提出SOX5作为克服BRCA1/2突变的乳腺癌和卵巢癌中PARP抑制剂耐药性的有前景的治疗靶点。
