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

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-...

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Published in	Cancer cell Vol. 20; no. 3; pp. 400 - 413
Main Authors	De Raedt, Thomas, Walton, Zandra, Yecies, Jessica L., Li, Danan, Chen, Yimei, Malone, Clare F., Maertens, Ophélia, Jeong, Seung Min, Bronson, Roderick T., Lebleu, Valerie, Kalluri, Raghu, Normant, Emmanuel, Haigis, Marcia C., Manning, Brendan D., Wong, Kwok-Kin, Macleod, Kay F., Cichowski, Karen
Format	Journal Article
Language	English
Published	United States Elsevier Inc 13.09.2011
Subjects	Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Benzoquinones - pharmacology Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism eIF-2 Kinase - antagonists & inhibitors eIF-2 Kinase - genetics Endoplasmic Reticulum - drug effects Fluorescent Antibody Technique Glutathione - antagonists & inhibitors Glutathione - biosynthesis HSP90 Heat-Shock Proteins - antagonists & inhibitors In Situ Nick-End Labeling Lactams, Macrocyclic - pharmacology Mice Mitochondria - drug effects Molecular Targeted Therapy Nerve Sheath Neoplasms - drug therapy Nerve Sheath Neoplasms - metabolism Oxidative Stress - drug effects Oxidative Stress - genetics Polymerase Chain Reaction Proto-Oncogene Proteins p21(ras) - metabolism ras Proteins - metabolism Reactive Oxygen Species - metabolism RNA Interference RNA, Small Interfering Sirolimus - pharmacology Tumor Cells, Cultured Tumor Suppressor Protein p53 - metabolism
Online Access	Get full text
ISSN	1535-6108 1878-3686 1878-3686
DOI	10.1016/j.ccr.2011.08.014

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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. ► We describe a promising combination therapy for two aggressive Ras-driven cancers ► mTOR and HSP90 inhibitors cooperate to exert potent activity in mouse models of MPNST and NSCLC ► These agents function by promoting irresolvable ER and oxidative stress ► Combinatorial therapy can capitalize on cellular vulnerabilities of cancer cells
AbstractList	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. ► We describe a promising combination therapy for two aggressive Ras-driven cancers ► mTOR and HSP90 inhibitors cooperate to exert potent activity in mouse models of MPNST and NSCLC ► These agents function by promoting irresolvable ER and oxidative stress ► Combinatorial therapy can capitalize on cellular vulnerabilities of cancer cells 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. 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.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. 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.
Author	Walton, Zandra Cichowski, Karen Wong, Kwok-Kin Li, Danan Chen, Yimei Bronson, Roderick T. Kalluri, Raghu Macleod, Kay F. Yecies, Jessica L. Malone, Clare F. Lebleu, Valerie Maertens, Ophélia Normant, Emmanuel Haigis, Marcia C. Manning, Brendan D. De Raedt, Thomas Jeong, Seung Min
AuthorAffiliation	3 Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA 02115 9 Infinity Pharmaceuticals, 780 Memorial Drive, Cambridge, MA 02139 5 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115 2 Harvard Medical School, Boston, MA, 02115, USA 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 8 Division of Matrix Biology, Beth Israel Deaconess Medical Center, Boston, MA 02115 6 The Ben May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637 7 Department of Pathology, Harvard Medical School, Boston, MA 02115 1 Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
AuthorAffiliation_xml	– name: 8 Division of Matrix Biology, Beth Israel Deaconess Medical Center, Boston, MA 02115 – name: 3 Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA 02115 – name: 6 The Ben May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637 – name: 7 Department of Pathology, Harvard Medical School, Boston, MA 02115 – name: 1 Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA – name: 2 Harvard Medical School, Boston, MA, 02115, USA – name: 9 Infinity Pharmaceuticals, 780 Memorial Drive, Cambridge, MA 02139 – name: 5 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115 – name: 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
Author_xml	– sequence: 1 givenname: Thomas surname: De Raedt fullname: De Raedt, Thomas organization: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA – sequence: 2 givenname: Zandra surname: Walton fullname: Walton, Zandra organization: Harvard Medical School, Boston, MA, 02115, USA – sequence: 3 givenname: Jessica L. surname: Yecies fullname: Yecies, Jessica L. organization: Harvard Medical School, Boston, MA, 02115, USA – sequence: 4 givenname: Danan surname: Li fullname: Li, Danan organization: Harvard Medical School, Boston, MA, 02115, USA – sequence: 5 givenname: Yimei surname: Chen fullname: Chen, Yimei organization: The Ben May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637 – sequence: 6 givenname: Clare F. surname: Malone fullname: Malone, Clare F. organization: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA – sequence: 7 givenname: Ophélia surname: Maertens fullname: Maertens, Ophélia organization: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA – sequence: 8 givenname: Seung Min surname: Jeong fullname: Jeong, Seung Min organization: Department of Pathology, Harvard Medical School, Boston, MA 02115 – sequence: 9 givenname: Roderick T. surname: Bronson fullname: Bronson, Roderick T. organization: Harvard Medical School, Boston, MA, 02115, USA – sequence: 10 givenname: Valerie surname: Lebleu fullname: Lebleu, Valerie organization: Harvard Medical School, Boston, MA, 02115, USA – sequence: 11 givenname: Raghu surname: Kalluri fullname: Kalluri, Raghu organization: Harvard Medical School, Boston, MA, 02115, USA – sequence: 12 givenname: Emmanuel surname: Normant fullname: Normant, Emmanuel organization: Infinity Pharmaceuticals, 780 Memorial Drive, Cambridge, MA 02139 – sequence: 13 givenname: Marcia C. surname: Haigis fullname: Haigis, Marcia C. organization: Department of Pathology, Harvard Medical School, Boston, MA 02115 – sequence: 14 givenname: Brendan D. surname: Manning fullname: Manning, Brendan D. organization: Harvard Medical School, Boston, MA, 02115, USA – sequence: 15 givenname: Kwok-Kin surname: Wong fullname: Wong, Kwok-Kin organization: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA – sequence: 16 givenname: Kay F. surname: Macleod fullname: Macleod, Kay F. organization: The Ben May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637 – sequence: 17 givenname: Karen surname: Cichowski fullname: Cichowski, Karen email: kcichowski@rics.bwh.harvard.edu organization: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/21907929$$D View this record in MEDLINE/PubMed
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Snippet	Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers:... Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1...
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SubjectTerms	Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Benzoquinones - pharmacology Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism eIF-2 Kinase - antagonists & inhibitors eIF-2 Kinase - genetics Endoplasmic Reticulum - drug effects Fluorescent Antibody Technique Glutathione - antagonists & inhibitors Glutathione - biosynthesis HSP90 Heat-Shock Proteins - antagonists & inhibitors In Situ Nick-End Labeling Lactams, Macrocyclic - pharmacology Mice Mitochondria - drug effects Molecular Targeted Therapy Nerve Sheath Neoplasms - drug therapy Nerve Sheath Neoplasms - metabolism Oxidative Stress - drug effects Oxidative Stress - genetics Polymerase Chain Reaction Proto-Oncogene Proteins p21(ras) - metabolism ras Proteins - metabolism Reactive Oxygen Species - metabolism RNA Interference RNA, Small Interfering Sirolimus - pharmacology Tumor Cells, Cultured Tumor Suppressor Protein p53 - metabolism
Title	Exploiting Cancer Cell Vulnerabilities to Develop a Combination Therapy for Ras-Driven Tumors
URI	https://dx.doi.org/10.1016/j.ccr.2011.08.014 https://www.ncbi.nlm.nih.gov/pubmed/21907929 https://www.proquest.com/docview/889177504 https://www.proquest.com/docview/907183779 https://pubmed.ncbi.nlm.nih.gov/PMC3233475
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