Constitutive NF-κB signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-κB-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β 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 GADD45β/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 invitro. Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.

Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors / L., Tornatore; A., Sandomenico*; Raimondo, Domenico; C., Low*; A., Rocci; C., Tralau Stewart; D., Capece; D'Andrea, Daniel; M., Bua; E., Boyle; M., Van Duin; P., Zoppoli; A., Jaxa Chamiec; A. K., Thotakura; J., Dyson; B. A., Walker; A., Leonardi; A., Chambery; C., Driessen; P., Sonneveld; G., Morgan; A., Palumbo; Tramontano, Anna; A., Rahemtulla; M., Ruvo; G., FranzosoThese authors contributed equally to the work. - In: CANCER CELL. - ISSN 1535-6108. - STAMPA. - 26:4(2014), pp. 495-508. [10.1016/j.ccr.2014.07.027]

Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors

RAIMONDO, Domenico;D'ANDREA, DANIEL;TRAMONTANO, ANNA;
2014

Abstract

Constitutive NF-κB signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-κB-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β 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 GADD45β/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 invitro. Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.
2014
kinase; inflammation; signaling pathway; mkk7/jnkk2; bortezomib; proteasome inhibitor; multiple-myeloma
01 Pubblicazione su rivista::01a Articolo in rivista
Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors / L., Tornatore; A., Sandomenico*; Raimondo, Domenico; C., Low*; A., Rocci; C., Tralau Stewart; D., Capece; D'Andrea, Daniel; M., Bua; E., Boyle; M., Van Duin; P., Zoppoli; A., Jaxa Chamiec; A. K., Thotakura; J., Dyson; B. A., Walker; A., Leonardi; A., Chambery; C., Driessen; P., Sonneveld; G., Morgan; A., Palumbo; Tramontano, Anna; A., Rahemtulla; M., Ruvo; G., FranzosoThese authors contributed equally to the work. - In: CANCER CELL. - ISSN 1535-6108. - STAMPA. - 26:4(2014), pp. 495-508. [10.1016/j.ccr.2014.07.027]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/655018
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