Cahuzac Maxime, Péant Benjamin, Mes-Masson Anne-Marie, Saad Fred
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.
Institut du Cancer de Montréal, Montreal, QC H2X0A9, Canada.
Cancers (Basel). 2022 Aug 11;14(16):3877. doi: 10.3390/cancers14163877.
Poly (ADP-ribose) polymerase inhibitors (PARPi) were initially deployed to target breast and ovarian tumors with mutations in DNA damage response genes. Recently, PARPi have been shown to be beneficial in the treatment of prostate cancer (PC) patients having exhausted conventional therapeutics. Despite demonstrating promising response rates, all patients treated with PARPi eventually develop resistance. However, PARPi resistance in PC is not well understood, and further studies are required to understand PARPi resistance in PC to propose strategies to circumvent resistance.
Starting from well-established olaparib-sensitive PC cell lines (LNCaP, C4-2B and DU145), we derived olaparib-resistant (OR) PC cell lines and performed a microarray analysis.
The olaparib IC50 values of OR cell lines increased significantly as compared to the parental cell lines. Gene expression analyses revealed that different pathways, including DNA repair, cell cycle regulation and autophagy, were affected by acquired resistance. A total of 195 and 87 genes were significantly upregulated and downregulated, respectively, in all three OR cell lines compared to their parental counterparts. Among these genes, we selected BRCC3, ROCK2 and ATG2B for validation. We showed that ROCK2 expression, basal autophagy and homologous recombination (HR) efficiency were increased in all OR cell lines.
Our study provides a new in vitro model to study PARPi resistance in PC and suggests new possible targets to reverse resistance and prolong the benefits of PARPi treatment.
聚（ADP - 核糖）聚合酶抑制剂（PARPi）最初用于靶向DNA损伤反应基因发生突变的乳腺癌和卵巢癌。最近，PARPi已被证明对常规治疗无效的前列腺癌（PC）患者有益。尽管显示出有前景的缓解率，但所有接受PARPi治疗的患者最终都会产生耐药性。然而，PC中的PARPi耐药性尚未得到很好的理解，需要进一步研究以了解PC中的PARPi耐药性，从而提出规避耐药性的策略。
从成熟的奥拉帕利敏感PC细胞系（LNCaP、C4 - 2B和DU145）开始，我们构建了奥拉帕利耐药（OR）PC细胞系并进行了微阵列分析。
与亲代细胞系相比，OR细胞系的奥拉帕利IC50值显著增加。基因表达分析表明，包括DNA修复、细胞周期调控和自噬在内的不同途径受到获得性耐药的影响。与亲代细胞系相比，在所有三个OR细胞系中，共有195个基因显著上调，87个基因显著下调。在这些基因中，我们选择BRCC3、ROCK2和ATG2B进行验证。我们发现所有OR细胞系中ROCK2表达、基础自噬和同源重组（HR）效率均增加。
我们的研究提供了一个新的体外模型来研究PC中的PARPi耐药性，并提出了新的可能靶点以逆转耐药性并延长PARPi治疗的益处。
