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

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 SCLC and potential therapeutic targets for this recalcitrant cancer.