title: In vitro multifaceted activities of a specific group of novel phosphatidylinositol 3-kinase inhibitors on hotspot mutant PIK3CA.
abstract: BACKGROUND
  As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in cancer, novel PI3K inhibitors such as ZSTK474, GDC-0941, NVP-BEZ235 and BKM-120 have been developed for cancer therapy. A high frequency of hotspot mutations known as E542K, E545K and H1047R in the PIK3CA gene, which encodes the catalytic subunit of PI3Kα, has been found in various types of human cancers. The hotspot PIK3CA mutations also lead to resistance to therapeutics targeting epidermal growth factor receptor (EGFR), further suggesting that inhibition of hotspot mutant PIK3CA be required for a PI3K inhibitor as anticancer drug candidate.
  
  
  METHODS
  To investigate the activity of the novel PI3K inhibitors on the hotspot mutant PIK3CA, we determined the inhibition against the respective recombinant mutant PI3Kαs by biochemical assay. We further examined the activity at cellular background by determining the effect on phosphorylation of Akt (Ser473), and that on the growth of cancer cells. In addition, apoptosis and autophagy in cells with or without hotspot PIK3CA mutation induced by the four inhibitors were investigated.
  
  
  RESULTS
  Our results indicated that each inhibitor exhibit comparable activity on the hotspot mutant PI3Kα to that on the wild type, which was further demonstrated by the cell-based assays. No clear correlation was shown between the PIK3CA genetic status and the sensitivity for apoptosis or autophagy induction. Interestingly, among the 4 PI3K inhibitors, BKM-120 is the weakest in PI3K inhibitory potency, but induces most potent apoptosis, suggesting that BKM-120 might have a unique mode of action.
  
  
  CONCLUSIONS
  Our result shows that the PI3K inhibitors exhibit potent activity on both hotspot mutant and wild type PI3Kα, suggesting they might be used to treat patients with or without PIK3CA mutation when approved.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences and Research Center of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai RD, Heping, Tianjin, 300070, China, kongdexin@tijmu.edu.cn.
authors.forename: Dexin
authors.initials: D
authors.lastname: Kong
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Kanami
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D053148:Caspase 3; D053179:Caspase 7; D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D007191:Indazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D013449:Sulfonamides; D014227:Triazines; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C571178:NVP-BKM120; C510150:ZSTK474; C484760:PIK3CA protein, human; C531198:dactolisib