INTRODUCTION ROS1-rearranged non-small cell lung cancer (NSCLC) has demonstrated promising response to lorlatinib; however, no targeted therapy is available after failure of lorlatinib and information on acquired resistance mechanisms mediating lorlatinib resistance among ROS1-rearranged NSCLC patients is limited. We report a ROS1-rearranged NSCLC patient who responded to immunochemotherapy after acquisition of ROS1 G2032K-mediated lorlatinib resistance. METHODS Next-generation sequencing (NGS) was performed on supraclavicular lymph nodes (SLN) and blood samples obtained from the 53-year old male patient with advanced CD74-ROS1-rearranged NSCLC. In vitro experiments with patient-derived SLN tumor cells and in silico homology modeling were performed to investigate mechanisms of G2032K-mediated inhibitor resistance. RESULTS NGS analysis revealed the detection of an acquired ROS1 G2032 K after failure from lorlatinib. Homology modeling revealed the conformational change in the inhibitor binding site induced by the ROS1 G2032 K that disrupted lorlatinib binding. In vitro experiments using patient-derived cells bearing concurrent CD74-ROS1-rearrangement and ROS1 G2032 K demonstrated half-maximal inhibitory concentration IC50 of 730.2 nM for lorlatinib, 812.1 nM for entrectinib, and 1546 nM for crizotinib, indicating resistance to these inhibitors. With PD-L1 expression of TPS 30 %, nab-paclitaxel plus pembrolizumab was administered as fifth-line treatment and achieved partial response, with sustained response ongoing for 7 months as of January 31, 2020. CONCLUSION ROS1 G2032 K is a novel mutation that mediates resistance to lorlatinib. With the lack of targeted therapeutic options after lorlatinib resistance, checkpoint inhibitor plus chemotherapy may be considered as a treatment option in patients with ROS1-rearranged NSCLC.

中文翻译：

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新型ROS1 G2032 K错义突变介导ROS1重排的肺腺癌患者的lorlatinib耐药性，但对nab-紫杉醇加pembrolizumab有反应。

简介ROS1重排非小细胞肺癌（NSCLC）已显示出对lorlatinib的有希望的反应。然而，在洛拉替尼治疗失败后，没有针对性的治疗方法可用，而且关于在ROS1重排的NSCLC患者中介导洛拉替尼耐药性的获得性耐药机制的信息有限。我们报道了一位ROS1重排的NSCLC患者，该患者在获得ROS1 G2032K介导的洛来替尼耐药性后对免疫化学疗法产生了反应。方法对53岁男性晚期CD74-ROS1重排NSCLC患者的锁骨上淋巴结（SLN）和血液样本进行了下一代测序（NGS）。进行了来自患者的SLN肿瘤细胞的体外实验和计算机模拟模型，以研究G2032K介导的抑制剂耐药性的机制。结果NGS分析显示，在从洛拉替尼治疗失败后检测到获得的ROS1 G2032K。同源性建模揭示了由ROS1 G2032 K诱导的抑制剂结合位点的构象变化，破坏了氯雷替尼的结合。使用带有并发CD74-ROS1重排和ROS1 G2032 K的患者来源细胞进行的体外实验显示，氯雷替尼的半最大抑制浓度IC50为730.2 nM，恩替替尼的最大抑制浓度为812.1 nM，克唑替尼的最大抑制浓度为1546 nM，表明对这些抑制剂具有耐药性。由于TPS的PD-L1表达为30％，纳布-紫杉醇联合派姆单抗作为五线治疗，已实现部分缓解，截至2020年1月31日持续进行了7个月。结论ROS1 G2032 K是一种新型突变介导对洛来替尼的耐药性。