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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2011 Sep 13

PMID 21907929

Citations 149

Authors

Thomas De Raedt

Zandra Walton

Jessica L Yecies

Danan Li

Yimei Chen

Clare F Malone

Ophelia Maertens

Seung Min Jeong

Roderick T Bronson

Valerie LeBleu

Raghu Kalluri

Emmanuel Normant

Marcia C Haigis

Brendan D Manning

Kwok-Kin Wong

Kay F Macleod

Karen Cichowski

Affiliations

Soon will be listed here.

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.

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