Qi Zhaochang, He Lifang, Xu Zemei, Luo Xi, Ji Likeng, Lin Chenting, Giuliano Armando E, Cui Xiaojiang, Deng Zihao, Wu Jundong, Lin Stanley Li, Cui Yukun
Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, China.
Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Cancer Res. 2025 Oct 15;85(20):3949-3965. doi: 10.1158/0008-5472.CAN-24-4751.
Base excision repair (BER), a critical pathway for repairing DNA single-strand breaks, is mediated by PARP, which plays a pivotal role in maintaining genomic stability. Targeting PARP with PARP inhibitors (PARPi) has emerged as an effective strategy for treating BRCA-mutated breast cancers characterized by homologous recombination deficiency. However, PARPi resistance remains a major challenge in the treatment of BRCA-mutated breast cancer. Using bioinformatics analysis and cellular-level experiments, we discovered that the RNA-binding protein PCBP2 contributes to resistance to the PARPi olaparib in BRCA-mutated breast cancer by increasing PARP1 expression via interference with the m6A methylation machinery. PCBP2 was upregulated in olaparib-resistant cells, and PCBP2 overexpression in BRCA-mutated breast cancer cells increased resistance to olaparib and enhanced cell proliferation under treatment. Mechanistically, PCBP2 directly interacted with PARP1 mRNA, inhibiting m6A methylation and stabilizing the mRNA. PCBP2-mediated upregulation of PARP1 enhanced DNA repair activity, contributing to olaparib resistance. Together, these findings unveil a mechanism by which PCBP2 upregulates PARP1 to promote olaparib resistance in BRCA-mutated breast cancer, indicating that targeting this pathway could represent a therapeutic strategy to overcome PARPi resistance in breast cancer.
PCBP2-induced suppression of m6A methylation increases PARP1 to promote DNA damage repair and confer resistance to olaparib in BRCA-mutated breast cancer, making PCBP2 a potential therapeutic target to enhance PARP inhibitor sensitivity.
碱基切除修复（BER）是修复DNA单链断裂的关键途径，由PARP介导，PARP在维持基因组稳定性中起关键作用。用PARP抑制剂（PARPi）靶向PARP已成为治疗具有同源重组缺陷特征的BRCA突变乳腺癌的有效策略。然而，PARPi耐药性仍然是BRCA突变乳腺癌治疗中的一个主要挑战。通过生物信息学分析和细胞水平实验，我们发现RNA结合蛋白PCBP2通过干扰m6A甲基化机制增加PARP1表达，从而导致BRCA突变乳腺癌对PARPi奥拉帕尼产生耐药性。PCBP2在奥拉帕尼耐药细胞中上调，在BRCA突变乳腺癌细胞中过表达PCBP2可增加对奥拉帕尼的耐药性，并在治疗下增强细胞增殖。机制上，PCBP2直接与PARP1 mRNA相互作用，抑制m6A甲基化并稳定mRNA。PCBP2介导的PARP1上调增强了DNA修复活性，导致奥拉帕尼耐药。总之，这些发现揭示了PCBP2上调PARP1以促进BRCA突变乳腺癌中奥拉帕尼耐药的机制，表明靶向该途径可能代表一种克服乳腺癌中PARPi耐药的治疗策略。
PCBP2诱导的m6A甲基化抑制增加PARP1，以促进DNA损伤修复并赋予BRCA突变乳腺癌对奥拉帕尼的耐药性，使PCBP2成为增强PARP抑制剂敏感性的潜在治疗靶点。
