title: 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.
authors: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
authors: Thomas
authors: T
authors: De Raedt
authors: Zandra
authors: Z
authors: Walton
authors: Jessica L
authors: JL
authors: Yecies
authors: Danan
authors: D
authors: Li
authors: Yimei
authors: Y
authors: Chen
authors: Clare F
authors: CF
authors: Malone
authors: Ophélia
authors: O
authors: Maertens
authors: Seung Min
authors: SM
authors: Jeong
authors: Roderick T
authors: RT
authors: Bronson
authors: Valerie
authors: V
authors: Lebleu
authors: Raghu
authors: R
authors: Kalluri
authors: Emmanuel
authors: E
authors: Normant
authors: Marcia C
authors: MC
authors: Haigis
authors: Brendan D
authors: BD
authors: Manning
authors: Kwok-Kin
authors: KK
authors: Wong
authors: Kay F
authors: KF
authors: Macleod
authors: Karen
authors: K
authors: Cichowski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016227:Benzoquinones / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D020287:In Situ Nick-End Labeling; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D058990:Molecular Targeted Therapy; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D016133:Polymerase Chain Reaction; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D005978:Glutathione; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D020123:Sirolimus; D016159:Tumor Suppressor Protein p53; D019892:eIF-2 Kinase; D018631:ras Proteins; C112765:tanespimycin; C495971:Hras protein, mouse