Characterization Of The Extrinsic And Intrinsic Signatures And Therapeutic Vulnerability Of Small Cell Lung Cancers Guizhen Wang Zheng Wang Shihao Bai Yun Tan Wenzhao Zhong Guogui Sun Yutao Liu Bo Pan Chen Huang Di Wang Beibei Sun Dongni Chen Bin Zhang Yongchun Zhou Sheng Li Xiangwei Zhang Sichong Han Fuying Yang by Gui-zhen Wang & Zheng Wang & Shi-hao Bai & Yun Tan & Wen-zhao Zhong & Guo-gui Sun & Yu-tao Liu & Bo Pan & Chen Huang & Di Wang & Bei-bei Sun & Dong-ni Chen & Bin Zhang & Yong-chun Zhou & Sheng Li & Xiang-wei Zhang & Si-chong Han & Fu-ying Yang &… instant download after payment.

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, ischaracterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-offunction 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 the190,313 SCLC cancer cells from 39 patients, with the ASCL1+SOX1+ stem-like cell cluster across SCLC subtypes. The majorhistocompatibility complex (MHC) class I molecules were expressed at low levels in six and high levels in five cancer cell clusters1234567890();,:and were inversely associated with the KI67 expression level. Abnormal splicing of mRNAs was a feature of SCLC, with focaladhesion 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 affectmicrobiota variance in SCLC. Taken together, our data further revealed the complicated ITH and discovered that FAK splicingvariants represent high-frequency gain-of-function alterations in oncogene in SCLC and potential therapeutic targets for thisrecalcitrant cancer.Signal Transduction and Targeted Therapy (2025) 10:290 ;