Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors

Thomas De Raedt; Zandra Walton; Jessica L. Yecies; Danan Li; Yimei Chen; Clare F. Malone; Ophélia 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

doi:10.1016/j.ccr.2011.08.014

Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors

Thomas De Raedt, Zandra Walton, Jessica L. Yecies, Danan Li, Yimei Chen, Clare F. Malone, Ophélia 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

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214 Scopus citations

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.

Original language	English
Pages (from-to)	400-413
Number of pages	14
Journal	Cancer Cell
Volume	20
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2011.08.014
State	Published - Sep 2011
Externally published	Yes

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De Raedt, T., Walton, Z., Yecies, J. L., Li, D., Chen, Y., Malone, C. F., Maertens, O., Jeong, S. M., Bronson, R. T., Lebleu, V., Kalluri, R., Normant, E., Haigis, M. C., Manning, B. D., Wong, K. K., Macleod, K. F., & Cichowski, K. (2011). Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell, 20(3), 400-413. https://doi.org/10.1016/j.ccr.2011.08.014

@article{c4929d53a1534c5abcf42686940beb4d,

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.",

author = "{De Raedt}, Thomas and Zandra Walton and Yecies, {Jessica L.} and Danan Li and Yimei Chen and Malone, {Clare F.} and Oph{\'e}lia Maertens and Jeong, {Seung Min} and Bronson, {Roderick T.} and Valerie Lebleu and Raghu Kalluri and Emmanuel Normant and Haigis, {Marcia C.} and Manning, {Brendan D.} and Wong, {Kwok Kin} and Macleod, {Kay F.} and Karen Cichowski",

note = "Funding Information: We thank Wade Harper, Steve Elledge, Nathanael Gray, Heather Harding, and Hugues de Th{\'e} for helpful discussions. This work was supported by the NCI KC: (CA129814) and the Ludwig Center at DF/HCC; KWW: (CA122794, CA140594). TD is a recipient of the Young Investigator Award of the Children's Tumor Foundation. OM is a Postdoctoral Fellow of the Research Foundation Flanders (FWO). ",

year = "2011",

month = sep,

doi = "10.1016/j.ccr.2011.08.014",

language = "English",

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De Raedt, T, Walton, Z, Yecies, JL, Li, D, Chen, Y, Malone, CF, Maertens, O, Jeong, SM, Bronson, RT, Lebleu, V, Kalluri, R, Normant, E, Haigis, MC, Manning, BD, Wong, KK, Macleod, KF & Cichowski, K 2011, 'Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors', Cancer Cell, vol. 20, no. 3, pp. 400-413. https://doi.org/10.1016/j.ccr.2011.08.014

TY - JOUR

T1 - Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors

AU - De Raedt, Thomas

AU - Walton, Zandra

AU - Yecies, Jessica L.

AU - Li, Danan

AU - Chen, Yimei

AU - Malone, Clare F.

AU - Maertens, Ophélia

AU - Jeong, Seung Min

AU - Bronson, Roderick T.

AU - Lebleu, Valerie

AU - Kalluri, Raghu

AU - Normant, Emmanuel

AU - Haigis, Marcia C.

AU - Manning, Brendan D.

AU - Wong, Kwok Kin

AU - Macleod, Kay F.

AU - Cichowski, Karen

N1 - Funding Information: We thank Wade Harper, Steve Elledge, Nathanael Gray, Heather Harding, and Hugues de Thé for helpful discussions. This work was supported by the NCI KC: (CA129814) and the Ludwig Center at DF/HCC; KWW: (CA122794, CA140594). TD is a recipient of the Young Investigator Award of the Children's Tumor Foundation. OM is a Postdoctoral Fellow of the Research Foundation Flanders (FWO).

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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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SN - 1535-6108

VL - 20

SP - 400

EP - 413

JO - Cancer Cell

JF - Cancer Cell

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ER -

Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors

Abstract

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