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Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.

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 - Cancer Cell (2014)

Bottom Line: 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.Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.

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GADD45B Is Highly Expressed in MM Cells and Associates with Aggressive Disease(A) qRT-PCR showing the GADD45B mRNA levels in monoclonal CD138+ cells from MM or MGUS patients and polyclonal CD138+ cells (normal). ∗∗∗p = 0.00018.(B and C) Progression-free survival (B) and OS (C), as defined by the International Myeloma Working Group Uniform Response Criteria (Kyle and Rajkumar, 2009), in MM patients with low or high GADD45B levels, as assessed by qRT-PCR, in CD138+ cells. Patients were from the velcade/melphalan/prednisone arm of the trial and stratified at diagnosis, using as a cutoff the median GADD45B expression value.See also Figure S1.
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fig1: GADD45B Is Highly Expressed in MM Cells and Associates with Aggressive Disease(A) qRT-PCR showing the GADD45B mRNA levels in monoclonal CD138+ cells from MM or MGUS patients and polyclonal CD138+ cells (normal). ∗∗∗p = 0.00018.(B and C) Progression-free survival (B) and OS (C), as defined by the International Myeloma Working Group Uniform Response Criteria (Kyle and Rajkumar, 2009), in MM patients with low or high GADD45B levels, as assessed by qRT-PCR, in CD138+ cells. Patients were from the velcade/melphalan/prednisone arm of the trial and stratified at diagnosis, using as a cutoff the median GADD45B expression value.See also Figure S1.

Mentions: Given their key role in oncogenesis, we sought to investigate the downstream mechanisms mediating NF-κB survival signaling in MM. Because this signaling involves the induction of antiapoptotic NF-κB target genes, and we had previously identified the GADD45-family gene, GADD45B, as a transcriptional target of NF-κB encoding a potent and selective inhibitor of the JNK MAPK pathway and, therefore, of apoptosis (De Smaele et al., 2001; Papa et al., 2004), we investigated the involvement of this gene in MM. GADD45B was markedly upregulated in monoclonal CD138+ PCs from MM patients compared with monoclonal PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition (Kyle and Rajkumar, 2009), or healthy polyclonal PCs (Figure 1A), thus establishing a correlation between GADD45B mRNA expression and PC malignancy. Strikingly, when MM patients were stratified at diagnosis on the basis of the GADD45B mRNA expression in CD138+ cells, the cohort of patients expressing high levels of GADD45B exhibited dramatically shorter progression-free survival and significantly shorter overall survival (OS) than the cohort of patients expressing low levels of GADD45B, despite both groups of patients having been treated with the same velcade/melphalan/prednisone protocol (Palumbo et al., 2010) (Figures 1B and 1C). A similar correlation of GADD45B expression with poor clinical outcome was observed using two independent gene expression data sets of newly diagnosed MM patients, thus providing external validation of our findings (Broyl et al., 2010; Dickens et al., 2010) (Figures S1A and S1B available online). Collectively, these results establish a strong correlation between GADD45B expression and disease progression in MM and identify GADD45β as a hallmark of more aggressive disease.


Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.

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 - Cancer Cell (2014)

GADD45B Is Highly Expressed in MM Cells and Associates with Aggressive Disease(A) qRT-PCR showing the GADD45B mRNA levels in monoclonal CD138+ cells from MM or MGUS patients and polyclonal CD138+ cells (normal). ∗∗∗p = 0.00018.(B and C) Progression-free survival (B) and OS (C), as defined by the International Myeloma Working Group Uniform Response Criteria (Kyle and Rajkumar, 2009), in MM patients with low or high GADD45B levels, as assessed by qRT-PCR, in CD138+ cells. Patients were from the velcade/melphalan/prednisone arm of the trial and stratified at diagnosis, using as a cutoff the median GADD45B expression value.See also Figure S1.
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Related In: Results  -  Collection

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fig1: GADD45B Is Highly Expressed in MM Cells and Associates with Aggressive Disease(A) qRT-PCR showing the GADD45B mRNA levels in monoclonal CD138+ cells from MM or MGUS patients and polyclonal CD138+ cells (normal). ∗∗∗p = 0.00018.(B and C) Progression-free survival (B) and OS (C), as defined by the International Myeloma Working Group Uniform Response Criteria (Kyle and Rajkumar, 2009), in MM patients with low or high GADD45B levels, as assessed by qRT-PCR, in CD138+ cells. Patients were from the velcade/melphalan/prednisone arm of the trial and stratified at diagnosis, using as a cutoff the median GADD45B expression value.See also Figure S1.
Mentions: Given their key role in oncogenesis, we sought to investigate the downstream mechanisms mediating NF-κB survival signaling in MM. Because this signaling involves the induction of antiapoptotic NF-κB target genes, and we had previously identified the GADD45-family gene, GADD45B, as a transcriptional target of NF-κB encoding a potent and selective inhibitor of the JNK MAPK pathway and, therefore, of apoptosis (De Smaele et al., 2001; Papa et al., 2004), we investigated the involvement of this gene in MM. GADD45B was markedly upregulated in monoclonal CD138+ PCs from MM patients compared with monoclonal PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition (Kyle and Rajkumar, 2009), or healthy polyclonal PCs (Figure 1A), thus establishing a correlation between GADD45B mRNA expression and PC malignancy. Strikingly, when MM patients were stratified at diagnosis on the basis of the GADD45B mRNA expression in CD138+ cells, the cohort of patients expressing high levels of GADD45B exhibited dramatically shorter progression-free survival and significantly shorter overall survival (OS) than the cohort of patients expressing low levels of GADD45B, despite both groups of patients having been treated with the same velcade/melphalan/prednisone protocol (Palumbo et al., 2010) (Figures 1B and 1C). A similar correlation of GADD45B expression with poor clinical outcome was observed using two independent gene expression data sets of newly diagnosed MM patients, thus providing external validation of our findings (Broyl et al., 2010; Dickens et al., 2010) (Figures S1A and S1B available online). Collectively, these results establish a strong correlation between GADD45B expression and disease progression in MM and identify GADD45β as a hallmark of more aggressive disease.

Bottom Line: 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.Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.

Show MeSH
Related in: MedlinePlus