Exploiting Cancer Cell Vulnerabilities to Develop a Combination Therapy for Ras-Driven Tumors

被引：207

作者：

De Raedt, Thomas ^{[1
,2
,3
]}

Walton, Zandra ^{[2
,4
]}

Yecies, Jessica L. ^{[2
,5
]}

Li, Danan ^{[2
,4
]}

Chen, Yimei ^{[6
]}

Malone, Clare F. ^{[1
,2
]}

Maertens, Ophelia ^{[1
,2
]}

Jeong, Seung Min ^{[7
]}

Bronson, Roderick T. ^{[2
]}

Lebleu, Valerie ^{[2
,8
]}

Kalluri, Raghu ^{[2
,8
]}

Normant, Emmanuel ^{[9
]}

Haigis, Marcia C. ^{[7
]}

Manning, Brendan D. ^{[2
,5
]}

Wong, Kwok-Kin ^{[1
,2
,3
]}

Macleod, Kay F. ^{[6
]}

Cichowski, Karen ^{[1
,2
,3
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

[3] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[6] Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA

[7] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[8] Beth Israel Deaconess Med Ctr, Div Matrix Biol, Boston, MA 02115 USA

[9] Infin Pharmaceut, Cambridge, MA 02139 USA

来源：

CANCER CELL | 2011年 / 20卷 / 03期

关键词：

ENDOPLASMIC-RETICULUM-STRESS; UNFOLDED PROTEIN RESPONSE; NEUROFIBROMATOSIS TYPE-1 GENE; OXIDATIVE STRESS; LUNG-CANCER; MUTATIONS; AUTOPHAGY; HSP90; SUPPRESSOR; REVEALS;

D O I：

10.1016/j.ccr.2011.08.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：400 / 413

页数：14

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