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

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.