Author/Authors :
Roper، نويسنده , , Jatin and Sinnamon، نويسنده , , Mark J. and Coffee، نويسنده , , Erin M. and Belmont، نويسنده , , Peter and Keung، نويسنده , , Lily and Georgeon-Richard، نويسنده , , Larissa and Wang، نويسنده , , Wei Vivian and Faber، نويسنده , , Anthony C. and Yun، نويسنده , , Jihye and Yilmaz، نويسنده , , ضmer H. and Bronson، نويسنده , , Roderick T. and Martin، نويسنده , , Eric S. and Tsichlis، نويسنده , , Philip N. and Hung، نويسنده , , Kenneth E.، نويسنده ,
Abstract :
PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.
Keywords :
PI3K , KRAS , Colorectal Cancer , Mouse model of cancer , MEK
