A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6

Baughn, Linda B.; Liberto, Maurizio Di; Wu, Kaida; Toogood, Peter L.; Louie, Tracey; Gottschalk, Rachel A.; Niesvizky, Rubén; Cho, Hearn; Ely, Scott; Moore, Malcolm A.S.; Chen‐Kiang, Selina

doi:10.1158/0008-5472.can-06-1098

Cited by 202 publications

(146 citation statements)

References 43 publications

Supporting

Mentioning

141

Contrasting

Order By: Relevance

“…However, exogenous TGF-␤ failed to augment the loss of viability in freshly isolated CD138 ϩ primary BM myeloma cells (n ϭ 4) during 24 h of ex vivo culturing, or to induce cell cycle arrest based on the analysis of BrdU uptake, when proliferation was extended transiently ex vivo in coculture with HS-5 BMSCs and cytokines (33) (Fig. 1B).…”

Section: Tgf-␤ Is Secreted By Bmscs But It Fails To Induce Growth Armentioning

confidence: 99%

CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells

Baughn

Liberto

Niesvizky

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Resistance to growth suppression by TGF-β1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-β-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-β activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G1 cyclin-dependent kinase (CDK) inhibitors (p15INK4b, p21CIP1/WAF1, p27KIP1, p57KIP2) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr8 (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-β resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-β resistance in multiple myeloma.

show abstract

Section: Tgf-␤ Is Secreted By Bmscs But It Fails To Induce Growth Armentioning

confidence: 99%

CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells

Baughn

Liberto

Niesvizky

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…More recently, specific inhibition of Cdk4/6 by PD 0332991, an orally bioavailable small-molecule Cdk inhibitor Preclinical activity of P276-00 in myeloma N Raje et al has demonstrated growth arrest in MM cells. 37 PD 0332991 in combination with steroids triggered MM cell apoptosis suggesting its utility with conventional and novel agents. Here we show that P276-00 induces apoptosis in the majority of MM cells.…”

Section: P276-00 Is Active In An MM Xenograft Modelmentioning

confidence: 99%

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

et al. 2009

View full text Add to dashboard Cite

Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in 450% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclindependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspasedependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

show abstract

“…5), (R)-roscovitine (CYC202/Seliciclib; refs. 11, 12), R547 (13,14), SNS-032 (15), PD-0332991 (16,17), AZD5438 (18,19), ZK 304709 (20,21), AG-024322, AT7519, and P276-00 (21).…”

Section: Introductionmentioning

confidence: 99%

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Bettayeb

Sallam

Ferandin

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6

Cited by 202 publications

References 43 publications

CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells

CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Contact Info

Product

Resources

About