Ganetespib radiosensitization for liver cancer therapy

ABSTRACTTherapies for liver cancerparticularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 ( HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancercells. HSP90client proteins include critical components of pathways implicated in liver cancercell survival and radioresistance. The effects of a novel non- geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancercell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancersurvival and radioresistance. We then evaluated tumor growth delayand effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. ...