Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy.
Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy.
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DOI：
10.1158/0008-5472.can-21-2964
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发表时间：
2022-02-01
期刊：
影响因子：
11.2
通讯作者：
Rudin CM
中科院分区：
文献类型：
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作者：
Quintanal-Villalonga A;Taniguchi H;Hao Y;Chow A;Zhan YA;Chavan SS;Uddin F;Allaj V;Manoj P;Shah NS;Chan JM;Offin M;Ciampricotti M;Ray-Kirton J;Egger J;Bhanot U;Linkov I;Asher M;Roehrl MH;Qiu J;de Stanchina E;Hollmann TJ;Koche RP;Sen T;Poirier JT;Rudin CM
小细胞肺癌（SCLC）是一种侵袭性的恶性肿瘤，其特征在于早期转移和极高的致死率。在过去的几十年里，SCLC治疗的支柱一直是基于铂的双重化疗，最近增加的免疫治疗在一部分患者中提供了适度的益处。然而，几乎所有接受全身治疗的患者都会迅速发展为耐药性疾病，并且缺乏针对复发性和进展性疾病的有效治疗方法。在这里，我们在代表不同分子亚型的多个SCLC细胞系中使用可药用基因组文库进行了CRISPR-Cas9筛选。该筛选指定由XPO 1编码的exportin-1作为治疗靶点。相对于其他肺癌组织学和其他肿瘤类型，XPO 1在SCLC中高度且普遍表达。XPO 1基因敲除增强了化疗敏感性，并且exportin-1抑制剂与一线和二线化疗均表现出协同作用。小分子exportin-1抑制剂selinexor联合顺铂或伊立替康分别显著抑制化疗无效和化疗复发SCLC患者来源的异种移植物中的肿瘤生长。总之，这些数据确定输出蛋白-1作为SCLC中有前途的治疗靶点，具有显著增强通常用于治疗这种疾病的细胞毒性剂的功效的潜力。
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1, as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease.