title: NVP-BKM120, a novel PI3K inhibitor, shows synergism with a STAT3 inhibitor in human gastric cancer cells harboring KRAS mutations.
abstract: Aberrations of Phosphoinositide 3-kinase (PI3K)/AKT signaling are frequently             observed in many types of cancer, promoting its emergence as a promising target             for cancer treatment. PI3K can become activated by various pathways, one of which             includes RAS. RAS can not only directly activate the PI3K/AKT pathway via binding             to p110 of PI3K, but also regulates mTOR via ERK or RSK independently of the PI3K/AKT             pathway. Thus, actively mutated RAS can constitutively activate PI3K signaling.             Additionally, in RAS tumorigenic transformation, signal transducer and activator             of transcription 3 (STAT3) has been known also to be required. In this study,             we examined the efficacy of NVP-BKM120, a pan-class I PI3K inhibitor in human             gastric cancer cells and hypothesized that the combined inhibition of PI3K and             STAT3 would be synergistic in KRAS mutant gastric cancer cells. NVP-BKM120 demonstrated             anti-proliferative activity in 11 human gastric cancer cell lines by decreasing             mTOR downstream signaling. But NVP-BKM120 treatment increased p-AKT by subsequent             abrogation of feedback inhibition by stabilizing insulin receptor substrate-1.             In KRAS mutant gastric cancer cells, either p-ERK or p-STAT3 was also increased             upon treatment of NVP-BKM120. The synergistic efficacy study demonstrated that             dual PI3K and STAT3 blockade showed a synergism in cells harboring mutated KRAS             by inducing apoptosis. The synergistic effect was not seen in KRAS wild-type cells.             Together, these findings suggest for the first time that the dual inhibition of             PI3K and STAT3 signaling may be an effective therapeutic strategy for KRAS mutant             gastric cancer patients.
authors.affiliation: Cancer Research Institute, Seoul National University College                     of Medicine, Seoul, Republic of Korea.
authors.forename: Eunju
authors.initials: E
authors.lastname: Park
authors.forename: Jinah
authors.initials: J
authors.lastname: Park
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C571178:NVP-BKM120; C494086:STAT3 protein, human; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide