title: The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations.
abstract: OBJECTIVE
  The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in the PI3K pathway.
  
  
  METHODS
  Kinase inhibitory activity was profiled in cell-free assays. A large panel of human breast, ovarian, prostate, and endometrial cancer cell lines, as well as xenograft models, were used to evaluate the antitumor activity of CH5132799, followed by analysis for genetic alterations. Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors.
  
  
  RESULTS
  CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.
  
  
  CONCLUSIONS
  CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings.
authors.affiliation: Pharmaceutical Research Department 2, Kamakura Research Laboratories, Chugai Pharmaceutical Co Ltd, Kamakura, Kanagawa, Japan. tanaka.hiroshi@chugai-pharm.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanimura
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujii
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Sakata
authors.forename: Yukako
authors.initials: Y
authors.lastname: Tachibana
authors.forename: Jun
authors.initials: J
authors.lastname: Ohwada
authors.forename: Hirosato
authors.initials: H
authors.lastname: Ebiike
authors.forename: Shino
authors.initials: S
authors.lastname: Kuramoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Morita
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
authors.forename: Osamu
authors.initials: O
authors.lastname: Kondoh
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C484760:PIK3CA protein, human; C559137:CH 5132799