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Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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M-Cdk Drives Transition Into Mitosis02:15

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Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
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Abnormal Proliferation02:23

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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DNA Damage can Stall the Cell Cycle02:37

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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

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Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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  1. Home
  3. Research Domains
  5. Biomedical And Clinical Sciences
  7. Oncology And Carcinogenesis
  9. Predictive And Prognostic Markers
  11. Molecular Consequences Of Acute Versus Chronic Cdk12 Loss In Prostate Carcinoma Nominates Distinct Therapeutic Strategies.
  1. Home
  3. Research Domains
  5. Biomedical And Clinical Sciences
  7. Oncology And Carcinogenesis
  9. Predictive And Prognostic Markers
  11. Molecular Consequences Of Acute Versus Chronic Cdk12 Loss In Prostate Carcinoma Nominates Distinct Therapeutic Strategies.

Related Experiment Video

Murine Prostate Micro-dissection and Surgical Castration
08:49

Murine Prostate Micro-dissection and Surgical Castration

Published on: May 11, 2016

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Molecular consequences of acute versus chronic CDK12 loss in prostate carcinoma nominates distinct therapeutic strategies.

Sander Frank1, Thomas Persse2, Ilsa Coleman1

  • 1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA 98119.

Biorxiv : the Preprint Server for Biology
|July 29, 2024

View abstract on PubMed

Summary
This summary is machine-generated.

Genomic loss of CDK12 in prostate cancer causes a temporary homologous recombination deficiency. However, cancer cells adapt, losing this deficiency and resisting PARP inhibitors, suggesting new therapeutic targets like CDK13.

Keywords:
CDK12DNA repairPARPprostate cancer

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Related Experiment Videos

Murine Prostate Micro-dissection and Surgical Castration
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Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

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Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Genomic loss of CDK12 kinase occurs in metastatic castration-resistant prostate cancer (mCRPC) and is linked to poor outcomes.
  • Acute CDK12 loss causes homologous recombination deficiency (HRd) via premature intronic polyadenylation (IPA) of HR genes.
  • mCRPC patients with CDK12 alterations have not benefited from HRd-targeting therapies like PARP inhibitors.

Purpose of the Study:

  • To investigate if the HRd phenotype is primarily a consequence of acute CDK12 loss.
  • To determine if this HRd effect diminishes in prostate cancers adapted to CDK12 loss.
  • To explore alternative therapeutic strategies for CDK12-altered mCRPC.

Main Methods:

  • Analysis of whole genome and RNA sequencing data from human mCRPCs.
tandem duplication
therapeutics
transcription
  • Experiments involving acute CDK12 inhibition and analysis of adapted mCRPC models.
  • Assessment of homologous recombination (HR) via RAD51 foci formation.
  • Evaluation of therapeutic responses to CDK12/13 inhibitors in xenograft models.

    • Main Results:

    • Tumors with biallelic CDK12 loss lacked HRd genomic scar signatures, despite exhibiting the tandem-duplicator phenotype.
    • Acute CDK12 inhibition caused aberrant polyadenylation and reduced expression of long HR genes, effects largely absent in adapted cells.
    • ATM gene showed persistent transcript shortening and reduced protein in adapted CDK12-loss models, but HR remained intact.
    • CDK12-altered cells showed vulnerability to CDK13 targeting, and in vivo studies demonstrated SR4835 efficacy in CDK12-altered xenografts.

    Conclusions:

    • Aberrant polyadenylation and HR gene downregulation are primarily consequences of acute CDK12 deficiency, compensated for in adapted cells.
    • This explains the limited benefit of PARP inhibitors in patients with CDK12 alterations.
    • Targeting CDK13 or transcription represents a promising therapeutic avenue for CDK12-altered mCRPC.