title: Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis.
abstract: BACKGROUND
  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 individual 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 comprehensive analysis could stratify SCLC patients by potential therapeutic targets.
authors.affiliation: *Division of Thoracic Oncology, National Cancer Center Hospital East; †Exploratory Oncology Research and Clinical Trial Center, National Cancer Center; ‡Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East; §Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan; and ‖Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Umemura
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Mimaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Makinoshima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tada
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ohmatsu
authors.forename: Seiji
authors.initials: S
authors.lastname: Niho
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morise
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.forename: Kanji
authors.initials: K
authors.lastname: Nagai
authors.forename: Reika
authors.initials: R
authors.lastname: Iwakawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Esumi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human