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Aberrations of Phosphoinositide 3-kinase (PI3K)/AKT signaling are frequentlyobserved in many types of cancer, promoting its emergence as a promising targetfor cancer treatment. PI3K can become activated by various pathways, one of whichincludes RAS. RAS can not only directly activate the PI3K/AKT pathway via bindingto p110 of PI3K, but also regulates mTOR via ERK or RSK independently of the PI3K/AKTpathway. Thus, actively mutated RAS can constitutively activate PI3K signaling.Additionally, in RAS tumorigenic transformation, signal transducer and activatorof 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 humangastric cancer cells and hypothesized that the combined inhibition of PI3K andSTAT3 would be synergistic in KRAS mutant gastric cancer cells. NVP-BKM120 demonstratedanti-proliferative activity in 11 human gastric cancer cell lines by decreasingmTOR downstream signaling. But NVP-BKM120 treatment increased p-AKT by subsequentabrogation of feedback inhibition by stabilizing insulin receptor substrate-1.In KRAS mutant gastric cancer cells, either p-ERK or p-STAT3 was also increasedupon treatment of NVP-BKM120. The synergistic efficacy study demonstrated thatdual PI3K and STAT3 blockade showed a synergism in cells harboring mutated KRASby 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 ofPI3K and STAT3 signaling may be an effective therapeutic strategy for KRAS mutantgastric cancer patients.

NVP-BKM120, a novel PI3K inhibitor, shows synergism with a STAT3 inhibitor in human gastric cancer cells harboring KRAS mutations