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首页> 外文期刊>Oncogene >RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients
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RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients

机译：RANBP9 影响癌细胞对遗传毒性应激的反应，其过表达与 NSCLC 患者对铂的反应较差有关

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Although limited by severe side effects and development of resistance platinum-based therapies still represent the most common first-line treatment for non-small cell lung cancer (NSCLC). However a crucial need in the clinical management of NSCLC is represented by the identification of cases sensitive to DNA damage response (DDR)-targeting drugs such as cisplatin or PARP inhibitors. Here we provide a molecular rationale for the stratification of NSCLC patients potentially benefitting from platinum compounds based on the expression levels of RANBP9 a recently identified player of the cellular DDR. RANBP9 was found overexpressed by immunohistochemistry (IHC) in NSCLC compared to normal adjacent tissues (NATs) (n = 147). Moreover a retrospective analysis of 132 platinum-treated patients from the multi-centric TAILOR trial showed that RANBP9 overexpression levels are associated with clinical response to platinum compounds Progression Free Survival Hazard Ratio ((RANBP9 high vs low) )1.73, 95 CI 1.15-2.59, p = 0.0084 Overall Survival HR (RANBP9 high vs low) 1.99, 95 CI 1.27-3.11, p = 0.003. Accordingly RANBP9 KO cells showed higher sensitivity to cisplatin in comparison with WT controls both in vitro and in vivo models. NSCLC RANBP9 KO cells were also more sensitive than control cells to the PARP inhibitor olaparib alone and in combination with cisplatin due to defective ATM-dependent and hyper-activated PARP-dependent DDR. The current investigation paves the way to prospective studies to assess the clinical value of RANBP9 protein levels as prognostic and predictive biomarker of response to DDR-targeting drugs leading to the development of new tools for the management of NSCLC patients.
机译：尽管受到严重副作用和耐药性发展的限制，但铂类疗法仍然是非小细胞肺癌（NSCLC）最常见的一线治疗药物。然而，NSCLC临床管理的一个关键需求是识别对DNA损伤反应（DDR）靶向药物（如顺铂或PARP抑制剂）敏感的病例。在这里，我们根据最近发现的细胞 DDR 参与者 RANBP9 的表达水平，为可能受益于铂化合物的 NSCLC 患者分层提供了分子基本原理。与正常邻近组织 （NAT） 相比，免疫组化 （IHC） 在 NSCLC 中发现 RANBP9 过表达 （n = 147）。此外，对来自多中心 TAILOR 试验的 132 名铂类治疗患者的回顾性分析表明，RANBP9 过表达水平与对铂类化合物的临床反应相关 [无进展生存风险比（（RANBP9 高与低））1.73,95% CI 1.15-2.59，p = 0.0084 总生存期 HR（RANBP9 高与低）1.99,95% CI 1.27-3.11，p = 0.003]。因此，与WT对照相比，RANBP9 KO细胞对顺铂的敏感性更高，无论是在体外还是体内模型中。NSCLC RANBP9 KO细胞对单独使用PARP抑制剂奥拉帕尼以及与顺铂联合使用也比对照细胞更敏感，因为存在缺陷的ATM依赖性和过度激活的PARP依赖性DDR。目前的研究为前瞻性研究铺平了道路，以评估 RANBP9 蛋白水平作为对 DDR 靶向药物反应的预后和预测生物标志物的临床价值，从而开发用于管理 NSCLC 患者的新工具。

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