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

2014; Elsevier BV; Volume: 9; Issue: 9 Linguagem: Inglês

10.1097/jto.0000000000000250

1556-1380

Shigeki Umemura, Sachiyo Mimaki, Hideki Makinoshima, Satoshi Tada, Genichiro Ishii, Hironobu Ohmatsu, Seiji Niho, Kiyotaka Yoh, Shingo Matsumoto, Akiko Takahashi, Masahiro Morise, Yuka Nakamura, Atsushi Ochiai, Kanji Nagai, Reika Iwakawa, Takashi Kohno, Jun Yokota, Yuichiro Ohe, Hiroyasu Esumi, Katsuya Tsuchihara, Kōichi Goto,

Lung Cancer Treatments and Mutations

IntroductionThe 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.MethodsWe 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.ResultsThe 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 individual changes in this pathway were mutually exclusive. Importantly, the SCLC cells harboring active PIK3CA mutations were potentially targetable with currently available PI3K inhibitors.ConclusionsThe PI3K/AKT/mTOR pathway is distinguishable in SCLC genomic alterations. Therefore, a sequencing-based comprehensive analysis could stratify SCLC patients by potential therapeutic targets.