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.

中文翻译：

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RANBP9影响癌细胞对遗传毒性应激的反应，其过表达与NSCLC患者对铂的不良反应有关。

尽管受严重的副作用和耐药性发展的限制，基于铂的疗法仍然代表着非小细胞肺癌（NSCLC）最常见的一线治疗。但是，NSCLC临床管理中的关键需求是确定对靶向DNA损伤反应（DDR）的药物（例如顺铂或PARP抑制剂）敏感的病例。在此，我们根据最近确定的细胞DDR分子RANBP9的表达水平，为可能受益于铂类化合物的NSCLC患者分层提供了分子基础。与正常邻近组织（NAT）相比，NSCLC中的RANBP9被免疫组织化学（IHC）表达过高（n = 147）。而且，_{（RANBP9高vs低）} 1.73，95％CI 1.15-2.59，p = 0.0084; 总生存率_{（RANBP9高vs低）} 1.99，95％CI 1.27-3.11，p = 0.003]。因此，与WT对照相比，在体外和体内模型中，RANBP9 KO细胞均显示出对顺铂更高的敏感性。由于缺陷性的ATM依赖性和过度活化的PARP依赖性DDR，NSCLC RANBP9 KO细胞还比对照细胞对单独的PARP抑制剂olaparib或与顺铂组合的敏感性更高。本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，从而导致开发了用于治疗NSCLC患者的新工具。