Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors

L Tornatore; A Sandomenico; D Raimondo; C Low; A Rocci; C Tralau-Stewart; D Capece; D D'Andrea; M Bua; E Boyle; Mark van Duin; P Zoppoli; A Jaxa-Chamiec; AK Thotakura; J Dyson; BA Walker; A Leonardi; A Chambery; Caroline Driessen; Pieter Sonneveld; G Morgan; A Palumbo; A Tramontano; A Rahemtulla; M Ruvo; G Franzoso

doi:10.1016/j.ccr.2014.07.027

Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors

L Tornatore, A Sandomenico, D Raimondo, C Low, A Rocci, C Tralau-Stewart, D Capece, D D'Andrea, M Bua, E Boyle, Mark van Duin, P Zoppoli, A Jaxa-Chamiec, AK Thotakura, J Dyson, BA Walker, A Leonardi, A Chambery, Caroline Driessen, Pieter SonneveldG Morgan, A Palumbo, A Tramontano, A Rahemtulla, M Ruvo, G Franzoso

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Abstract

Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45 beta/ MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.

Original language	Undefined/Unknown
Pages (from-to)	495-508
Number of pages	14
Journal	Cancer Cell
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2014.07.027
Publication status	Published - 2014

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EMC MM-02-41-03

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Cite this

Tornatore, L., Sandomenico, A., Raimondo, D., Low, C., Rocci, A., Tralau-Stewart, C., Capece, D., D'Andrea, D., Bua, M., Boyle, E., van Duin, M., Zoppoli, P., Jaxa-Chamiec, A., Thotakura, AK., Dyson, J., Walker, BA., Leonardi, A., Chambery, A., Driessen, C., ... Franzoso, G. (2014). Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors. Cancer Cell, 26(4), 495-508. https://doi.org/10.1016/j.ccr.2014.07.027

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title = "Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors",

abstract = "Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45 beta/ MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.",

author = "L Tornatore and A Sandomenico and D Raimondo and C Low and A Rocci and C Tralau-Stewart and D Capece and D D'Andrea and M Bua and E Boyle and {van Duin}, Mark and P Zoppoli and A Jaxa-Chamiec and AK Thotakura and J Dyson and BA Walker and A Leonardi and A Chambery and Caroline Driessen and Pieter Sonneveld and G Morgan and A Palumbo and A Tramontano and A Rahemtulla and M Ruvo and G Franzoso",

year = "2014",

doi = "10.1016/j.ccr.2014.07.027",

language = "Undefined/Unknown",

volume = "26",

pages = "495--508",

journal = "Cancer Cell",

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Tornatore, L, Sandomenico, A, Raimondo, D, Low, C, Rocci, A, Tralau-Stewart, C, Capece, D, D'Andrea, D, Bua, M, Boyle, E, van Duin, M, Zoppoli, P, Jaxa-Chamiec, A, Thotakura, AK, Dyson, J, Walker, BA, Leonardi, A, Chambery, A, Driessen, C, Sonneveld, P, Morgan, G, Palumbo, A, Tramontano, A, Rahemtulla, A, Ruvo, M & Franzoso, G 2014, 'Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors', Cancer Cell, vol. 26, no. 4, pp. 495-508. https://doi.org/10.1016/j.ccr.2014.07.027

TY - JOUR

T1 - Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors

AU - Tornatore, L

AU - Sandomenico, A

AU - Raimondo, D

AU - Low, C

AU - Rocci, A

AU - Tralau-Stewart, C

AU - Capece, D

AU - D'Andrea, D

AU - Bua, M

AU - Boyle, E

AU - van Duin, Mark

AU - Zoppoli, P

AU - Jaxa-Chamiec, A

AU - Thotakura, AK

AU - Dyson, J

AU - Walker, BA

AU - Leonardi, A

AU - Chambery, A

AU - Driessen, Caroline

AU - Sonneveld, Pieter

AU - Morgan, G

AU - Palumbo, A

AU - Tramontano, A

AU - Rahemtulla, A

AU - Ruvo, M

AU - Franzoso, G

PY - 2014

Y1 - 2014

N2 - Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45 beta/ MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.

AB - Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45 beta/ MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.

U2 - 10.1016/j.ccr.2014.07.027

DO - 10.1016/j.ccr.2014.07.027

M3 - Article

C2 - 25314077

SN - 1535-6108

VL - 26

SP - 495

EP - 508

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -