Small cell lung cancer (SCLC) is a fast-growing and malignant cancer that responds well to chemotherapy; however, the survival rate is less than 15% after 2 years of diagnosis. Therefore, novel therapeutic agents for treating SCLC patients need to be evaluated. This study aims to identify the therapeutic targets based on the comprehensive genomic profiling of SCLC patients. Among the molecular-profiled SCLC samples obtained using targeted sequencing, the array-based comparative genomic hybridization (array CGH) identified focal insulin receptor substrate 2 (IRS2) amplification in the SCLC patients. IRS2 amplification was confirmed in 5% of 73 SCLC patients. To determine whether IRS2 amplification could act as a therapeutic target, we generated a patient-derived xenograft (PDX) model and subsequently screened 43 targeted agents using the PDX-derived cells (PDCs). Ceritinib significantly inhibited the cell growth and impaired the tumor sphere formation in IRS2-expressing PDCs. Its effects were confirmed in various in vitro assays and were further validated in the mouse xenograft models. In this study, we present that IRS2 amplification and/or expression serve as preclinical implications for a novel therapeutic target in SCLC progression. Furthermore, we suggest that insulin-like growth factor-1 (IGF-1) receptor inhibitor-based therapy could be used for treating SCLC with IRS2 amplification.

小细胞肺癌（SCLC）是一种快速生长的恶性肿瘤，对化疗反应良好；但是，经过2年的诊断，存活率低于15％。因此，需要评估用于治疗SCLC患者的新型治疗剂。这项研究旨在根据SCLC患者的综合基因组概况来确定治疗目标。在使用靶向测序获得的分子谱SCLC样品中，基于阵列的比较基因组杂交（阵列CGH）鉴定了SCLC患者中的局灶性胰岛素受体底物2（IRS2）扩增。在73例SCLC患者中，有5％证实了IRS2扩增。确定是否IRS2扩增可以作为治疗目标，我们生成了患者衍生的异种移植（PDX）模型，随后使用PDX衍生的细胞（PDC）筛选了43种靶向药物。Ceritinib显着抑制了表达IRS2的PDC中的细胞生长并损害了肿瘤球的形成。它的作用在各种体外试验中得到了证实，并在小鼠异种移植模型中得到了进一步验证。在这项研究中，我们目前提出IRS2扩增和/或表达作为SCLC进展中新型治疗靶点的临床前意义。此外，我们建议基于胰岛素样生长因子-1（IGF-1）受体抑制剂的治疗可用于治疗IRS2扩增的SCLC 。