Therapeutic Priority of the PI3K/AKT/mTOR Pathway in Small Cell Lung Cancers as Revealed by a Comprehensive Genomic Analysis

Introduction: The information regarding therapeutically relevant genomic alterations in small cell lung cancer (SCLC) is not well developed. We analyzed the SCLC genome using an integrative approach to stratify the targetable alterations. Methods: We performed whole exon sequencing (n = 51) and copy number analysis (n =47) on surgically resected tumors and matched normal tissue samples from treatment-naive Japanese SCLC patients. Results: The demographics of the 51 patients included in this study were as follows: median age, 67 years (range, 42-86 years); female, 9 (18%); history of smoking, 50 (98%); and pathological stage I/II/III/ IV, 28/13/9/1, respectively. The average number of nonsynonymous mutations was 209 (range, 41-639; standard deviation, 130). We repeatedly confirmed the high prevalence of inactivating mutations in TP53 and RB1, and the amplification of MYC family members. In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 36% of the tumors: PIK3CA, 6%; PTEN, 4%; AKT2, 9%; AKT3, 4%; RICTOR, 9%; and mTOR, 4%. Furthermore, the indi- vidual changes in this pathway were mutually exclusive. Importantly, the SCLC cells harboring active PIK3CA mutations were potentially targetable with currently available PI3K inhibitors. Conclusions: The PI3K/AKT/mTOR pathway is distinguishable in SCLC genomic alterations. Therefore, a sequencing-based compre- hensive analysis could stratify SCLC patients by potential therapeu- tic targets.