ArticleBlood2012
Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.
Article in Blood, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 110 citations in OpenAlex.
- Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges.JCO precision oncology · 2022Pooled it
- Trial
- Palbociclib in combination with dexamethasone, bortezomib, and doxorubicin for pediatric relapsed acute lymphoblastic leukemia.Blood neoplasia · 2026Article
- Cell size-dependent mRNA transcription drives proteome remodeling.Cell reports · 2026Article
- CDK inhibitors promote neuroblastoma cell differentiation and increase sensitivity to retinoic acid-a promising combination strategy for therapeutic intervention.Cell death discovery · 2025Article
- Ribociclib in Sequential Combination with Doxorubicin in Anthracycline-Naïve Advanced Soft-Tissue Sarcomas: Results of a Dose-Finding Phase Ib Study.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Predictors of response to venetoclax and therapeutic potential of CDK7 inhibition in multiple myeloma.Blood neoplasia · 2024Article
- Palbociclib as an Antitumor Drug: A License to Kill.Molecules (Basel, Switzerland) · 2024Review
- The significance ofFrontiers in immunology · 2024Review
- CDK6 protein expression is associated with disease progression and treatment resistance in multiple myeloma.HemaSphere · 2024Article
- IMiD-Free Interval and IMiDs Sequence: Which Strategy Is Better Suited for Lenalidomide-Refractory Myeloma?Life (Basel, Switzerland) · 2023Review
- Aberrant APOBEC3B Expression in Breast Cancer Is Linked to Proliferation and Cell Cycle Phase.Cells · 2023Article
- Malignant clonal evolution drives multiple myeloma cellular ecological diversity and microenvironment reprogramming.Molecular cancer · 2022Article
- Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic leukemia.Haematologica · 2022Article
- Remote ischemic preconditioning causes transient cell cycle arrest and renal protection by a NF-κB-dependent Sema5B pathway.JCI insight · 2022Article
- microRNA-155-5p initiates childhood acute lymphoblastic leukemia by regulating the IRF4/CDK6/CBL axis.Laboratory investigation; a journal of technical methods and pathology · 2022Article
- Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma.Nature communications · 2022Article
- Role of ARK5 in cancer and other diseases (Review).Experimental and therapeutic medicine · 2021Review
- Simulated Microgravity Inhibits the Proliferation of Chang Liver Cells by Attenuation of the Major Cell Cycle Regulators and Cytoskeletal Proteins.International journal of molecular sciences · 2021Article
- Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption.Cell stem cell · 2021Article
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 1 country.
Funding
Abstract
Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.