Author/Authors :
De Raedt، نويسنده , , Thomas and Walton، نويسنده , , Zandra and Yecies، نويسنده , , Jessica L. and Li، نويسنده , , Danan and Chen، نويسنده , , Yimei and Malone، نويسنده , , Clare F. and Maertens، نويسنده , , Ophélia and Jeong، نويسنده , , Seung Min and Bronson، نويسنده , , Roderick T. and Lebleu، نويسنده , , Valerie and Kalluri، نويسنده , , Raghu and Normant، نويسنده , , Emmanuel and Haigis، نويسنده , , Marcia C. and Manning، نويسنده , , Brendan D. and Wong، نويسنده , , Kwok-Kin and Macleod، نويسنده , , Kay F. and Cichowski، نويسنده , , Karen، نويسنده ,
Abstract :
Summary
iven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1-deficient malignancies and Kras/p53 mutant lung cancer. We show that agents that enhance proteotoxic stress, including the HSP90 inhibitor IPI-504, induce tumor regression in aggressive mouse models, but only when combined with rapamycin. These agents synergize by promoting irresolvable ER stress, resulting in catastrophic ER and mitochondrial damage. This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations.
