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

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<sup>+</sup>/MKI67<sup>+</sup> and ASCL1<sup>+</sup>/CRIP2<sup>+</sup> clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the ASCL1<sup>+</sup>SOX1<sup>+</sup> 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.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-09-09
DOI
https://doi.org/10.1038/s41392-025-02378-6
Citations
5
Primary Topic
Lung Cancer Research Studies
Type
article
Field-Weighted Citation Impact
5.23
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article

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

Jianming Ying, Dongni Chen, Dawei Xie, Guang‐Biao Zhou et al.
5 citations
Signal Transduction and Targeted Therapy
Lung Cancer Research Studies
5.23
article

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

Jianming Ying, Dongni Chen, Dawei Xie, Guang‐Biao Zhou, Manli Wang, Xueyan Shi, Yongchun Zhou, Bo Pan, Si-Chong Han, Yunchao Huang, Xiang-Wei Zhang, Shihao Bai, Yun Tan, Guogui Sun, Yan Wang, Beibei Sun, Wen‐Zhao Zhong, Zhesheng Wen, Zheng Wang, Chong Chen, Sheng Li, Bin Zhang, Di Wang, Yutao Liu, Li Zhang, Na Wang, Ying Dong, Changli Wang, Ze‐Guang Han, Fuying Yang, Guizhen Wang, Mingkun Li, Lijun Liang, Yan Yu, Chen Huang, Yu‐Ke Shen, Hongbin Ji, Xiao‐Liang Jie, Jinsong Liu
article en
5 citations

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<sup>+</sup>/MKI67<sup>+</sup> and ASCL1<sup>+</sup>/CRIP2<sup>+</sup> clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the ASCL1<sup>+</sup>SOX1<sup>+</sup> 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.

Signal Transduction and Targeted TherapyVol. 10(1)
North China University of Science and Technology (CN), Harbin Medical University (CN), Sun Yat-sen University (CN), Shanghai Jiao Tong University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Sichuan University (CN), Kunming Medical University (CN), Ruijin Hospital (CN), Beijing Institute of Genomics (CN), Guangzhou Institutes of Biomedicine and Health (CN), Tianjin Medical University Cancer Institute and Hospital (CN), National Cancer Center (US), Henan Academy of Sciences (CN), Peking University Cancer Hospital (CN), Third Affiliated Hospital of Harbin Medical University (CN), North China University of Science and Technology Affiliated Hospital (CN), Shandong Provincial Hospital (CN), Center for Excellence in Molecular Cell Science (CN), Guangdong Academy of Medical Sciences (CN), Sun Yat-sen University Cancer Center (CN), Shanghai Institute of Hematology (CN), Guangdong Provincial People's Hospital (CN), State Key Laboratory of Respiratory Disease (CN), Second Affiliated Hospital of Zhejiang University (CN), Shandong First Medical University (CN), State Key Laboratory of Biotherapy, Southern Medical University (CN)
Openalex Percentile: Top 4%
Lung Cancer Research Studies
5.23
DOIOpen Access PDFOpenAlex
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