Wang Gui-Zhen, Wang Zheng, Bai Shi-Hao, Tan Yun, Zhong Wen-Zhao, Sun Guo-Gui, Liu Yu-Tao, Pan Bo, Huang Chen, Wang Di, Sun Bei-Bei, Chen Dong-Ni, Zhang Bin, Zhou Yong-Chun, Li Sheng, Zhang Xiang-Wei, Han Si-Chong, Yang Fu-Ying, Shi Xue-Yan, Jie Xiao-Liang, Shen Yu-Ke, Liang Li-Jun, Wen Zhe-Sheng, Zhang Li, Li Ming-Kun, Wang Na, Liu Jin-Song, Dong Ying, Wang Man-Li, Wang Yan, Wang Chang-Li, Xie Da-Wei, Han Ze-Guang, Ying Jian-Ming, Chen Chong, Huang Yun-Chao, Ji Hong-Bin, Zhang Yuan-Yuan, Yu Yan, Zhou Guang-Biao
State Key Laboratory of Molecular Oncology & Department of Medical Oncology & Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Signal Transduct Target Ther. 2025 Sep 10;10(1):290. doi: 10.1038/s41392-025-02378-6.
Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the ASCL1/MKI67 and ASCL1/CRIP2 clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the ASCL1SOX1 stem-like cell cluster across SCLC subtypes. The major histocompatibility complex (MHC) class I molecules were expressed at low levels in six and high levels in five cancer cell clusters and were inversely associated with the KI67 expression level. Abnormal splicing of mRNAs was a feature of SCLC, with focal adhesion kinase (FAK) splicing variants identified in 119 (77.3%) of 154 patients. FAK variants exhibited elevated kinase activity, were associated with the worst prognosis, and were sensitive to FAK inhibitors in patient-derived organoids and xenograft models. Eleven high-frequency mutations were identified in addition to TP53 and RB1, and smoking status and tumor stage did not affect microbiota variance in SCLC. Taken together, our data further revealed the complicated ITH and discovered that FAK splicing variants represent high-frequency gain-of-function alterations in oncogene in SCLC and potential therapeutic targets for this recalcitrant cancer.
小细胞肺癌（SCLC）是一种侵袭性神经内分泌肿瘤，与接触烟草致癌物密切相关，其特点是早期转移且预后不佳，五年总生存率低于7%。癌基因高频功能获得性突变鲜有报道，SCLC中的肿瘤内异质性（ITH）仍有待确定。在此，通过对314例SCLC进行多组学分析，我们发现ASCL1/MKI67和ASCL1/CRIP2簇占来自39例患者的190313个SCLC癌细胞的74.38%，ASCL1/SOX1干细胞样簇存在于所有SCLC亚型中。主要组织相容性复合体（MHC）I类分子在六个癌细胞簇中低表达，在五个癌细胞簇中高表达，且与KI67表达水平呈负相关。mRNA异常剪接是SCLC的一个特征，在154例患者中有119例（77.3%）检测到粘着斑激酶（FAK）剪接变体。FAK变体表现出升高的激酶活性，与最差的预后相关，并且在患者来源的类器官和异种移植模型中对FAK抑制剂敏感。除TP53和RB1外，还鉴定出11个高频突变，吸烟状态和肿瘤分期不影响SCLC中的微生物群差异。综上所述，我们的数据进一步揭示了复杂的ITH，并发现FAK剪接变体代表SCLC中癌基因的高频功能获得性改变以及这种难治性癌症的潜在治疗靶点。
