Song Chunyan, Lin Yaying, Cai Chujun, Tao Kangjia, Tan Jiahong, Xiong Kairong, Yang Wen, Chi Jianhua, Peng Zikun, Zhao Guangnian, Xia Yu, Fang Yong, Ma Ding, Gao Qinglei, Liu Dan
National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oncogene. 2025 May 31. doi: 10.1038/s41388-025-03466-1.
Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of homologous recombination-deficient (HRD) tumors, yet their efficacy in homologous recombination-proficient (HRP) tumors is still limited. Here, we pinpoint lysyl oxidase-like 2 (LOXL2) as a key epigenetic regulator driving PARPi resistance. Our study demonstrate that elevated LOXL2 expression correlates with poor prognosis and disease recurrence in high-grade serous ovarian cancer (HGSOC) patients. Functional studies reveal that LOXL2 depletion or pharmacological inhibition synergizes with PARPi to suppress HRP models of both ovarian and breast cancer. Mechanistically, LOXL2 directly interacts with and transcriptionally activates BRD4, a core component of the super-enhancer complex, thereby amplifying the expression of DNA damage repair (DDR) genes such as MDC1, KAT5, and USP7. Strikingly, LOXL2 inhibition induces a "BRCAness" phenotype in HRP tumors, rendering them more susceptible to PARPi by impairing DDR capacity. Combining BET inhibitors with PARPi abrogates LOXL2-mediated resistance, underscoring BRD4 dependency in this process. Our findings establish LOXL2 as a druggable epigenetic target to overcome PARPi resistance in HRP models of multiple tumor types, presenting a therapeutic strategy independent of HR status and holding significant clinical potential for expanding PARPi benefits to a broader patient population.
聚（ADP - 核糖）聚合酶抑制剂（PARPi）彻底改变了同源重组缺陷（HRD）肿瘤的治疗方式，但其在同源重组 proficient（HRP）肿瘤中的疗效仍然有限。在此，我们确定赖氨酰氧化酶样2（LOXL2）是驱动PARPi耐药的关键表观遗传调节因子。我们的研究表明，LOXL2表达升高与高级别浆液性卵巢癌（HGSOC）患者的不良预后和疾病复发相关。功能研究表明，LOXL2缺失或药物抑制与PARPi协同作用，可抑制卵巢癌和乳腺癌的HRP模型。机制上，LOXL2直接与超级增强子复合体的核心成分BRD4相互作用并转录激活它，从而放大DNA损伤修复（DDR）基因如MDC1、KAT5和USP7的表达。引人注目的是，LOXL2抑制在HRP肿瘤中诱导出“BRCAness”表型，通过损害DDR能力使其对PARPi更敏感。将BET抑制剂与PARPi联合使用可消除LOXL2介导的耐药性，强调了BRD4在此过程中的依赖性。我们的研究结果确定LOXL2是一个可药物靶向的表观遗传靶点，用于克服多种肿瘤类型HRP模型中的PARPi耐药性，提出了一种独立于HR状态的治疗策略，对将PARPi的益处扩展到更广泛的患者群体具有重大临床潜力。
