Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors
- PMID: 21907929
- PMCID: PMC3233475
- DOI: 10.1016/j.ccr.2011.08.014
Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors
Abstract
Ras-driven 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.
Copyright © 2011 Elsevier Inc. All rights reserved.
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Comment in
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Ras, ROS and proteotoxic stress: a delicate balance.Cancer Cell. 2011 Sep 13;20(3):281-2. doi: 10.1016/j.ccr.2011.08.020. Cancer Cell. 2011. PMID: 21907917 Free PMC article.
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