Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers

作者：Guizhen Wang, Zheng Wang, Shihao Bai, Yun Tan, Wen‐Zhao Zhong, Guogui Sun, Yutao Liu, Bo Pan, Chen Huang, Di Wang, Beibei Sun, Dongni Chen, Bin Zhang, Yongchun Zhou, Sheng Li, Xiang-Wei Zhang, Si-Chong Han, Fuying Yang, Xueyan Shi, Xiao‐Liang Jie, Yu‐Ke Shen, Lijun Liang, Zhesheng Wen, Li Zhang, Mingkun Li, Na Wang, Jinsong Liu, Ying Dong, Manli Wang, Yan Wang, Changli Wang, Dawei Xie, Ze‐Guang Han, Jian-Ming Ying, Chong Chen, Yunchao Huang, Hongbin Ji, Yuan-Yuan Zhang, Yan Yu, Guang‐Biao Zhou · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02378-6 · 被引用次数：12 · 研究领域：Lung Cancer Research Studies、Cancer Mechanisms and Therapy、Lung Cancer Treatments and Mutations

Abstract 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 ASCL1 + SOX1 + 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 S...