TY - JOUR T1 - Sorafenib/Regorafenib and PI3K/AKT Inhibition Interact to Kill Tumor Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.088005 SP - mol.113.088005 AU - Gangadharan B Sajithlal AU - Hossein A Hamed AU - Nichola Cruickshanks AU - Laurence Booth AU - Seyedmehrad Tavallai AU - Jahangir Syed AU - Steven Grant AU - Andrew Poklepovic AU - Paul Dent Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/07/22/mol.113.088005.abstract N2 - The present studies were to determine whether the multi-kinase inhibitors sorafenib/regorafenib cooperated with clinically relevant PI3K-AKT inhibitors to kill tumor cells. In liver, colorectal, lung, breast, kidney and brain cancer cells, at clinically achievable doses, sorafenib/regorafenib and the PI3K inhibitor PX-866 cooperated in a greater than additive fashion to kill tumor cells. Cells lacking PTEN were as sensitive to the drug combination as cells expressing the protein. Similar data were obtained using the AKT inhibitors perifosine and MK2206. PX-866 treatment abolished AKT / GSK3 phosphorylation and cell killing correlated with reduced activity of AKT and mTOR. Expression of activated AKT and to a lesser extent activated mTOR reduced drug combination lethality. Expression of BCL-XL or dominant negative caspase 9, but not c-FLIP-s, protected cells from the drug combination. Treatment of cells with PX-866 increased protein levels of p62, LAMP2 and LC3 and LC3II that correlated with a large increase in LC3-GFP vesicle numbers. Exposure of PX-866 treated cells to sorafenib reduced p62 and LAMP2 levels, decreased the ratio of LC3:LC3II and reduced LC3-GFP vesicle levels. Knock down of Beclin1 or ATG5 suppressed drug toxicity by ~40%. In vivo, sorafenib and PX-866 or regorafenib and MK2206 cooperated to suppress the growth of established HuH7 and HCT116 tumors, respectively. Collectively our data demonstrate that the combination of sorafenib family kinase inhibitors with inhibitors of the PI3K/AKT pathway kills tumor cells in vitro and in vivo. ER -