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Related Experiment Videos

ONYX-015 selectivity and the p14ARF pathway.

F McCormick1

  • 1Cancer Research Institute, UCSF Comprehensive Cancer Center, 94115, USA.

Oncogene
|June 28, 2001
PubMed
Summary
This summary is machine-generated.

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ONYX-015, a modified adenovirus, replicates in tumor cells by evading the p53 tumor suppressor pathway. This evasion mechanism involves disruptions in p14ARF and elevated Mdm2 activity, preventing p53 accumulation in cancer cells.

Area of Science:

  • Oncolytic virology
  • Molecular oncology
  • Gene therapy

Background:

  • ONYX-015 (dl1520) is an adenovirus engineered to lack the E1B 55K gene.
  • This genetic modification impairs its ability to neutralize the p53 tumor suppressor protein.
  • Adenoviruses typically hijack cellular machinery; ONYX-015's modification alters its interaction with host cell pathways.

Purpose of the Study:

  • To investigate the replication mechanism of ONYX-015 in different cell types.
  • To elucidate the role of p53 and its regulatory proteins in ONYX-015 replication.
  • To understand why ONYX-015 replicates in tumor cells but not primary epithelial cells.

Main Methods:

  • Infection of primary epithelial cells and tumor cells with ONYX-015.
  • Analysis of p53 protein levels and activity post-infection.

Related Experiment Videos

  • Investigation of the p14ARF and Mdm2 pathways in infected cells.
  • Assessment of viral replication efficiency in various cell lines.

    • Main Results:

    • ONYX-015 replicates inefficiently in primary epithelial cells, inducing high p53 levels.
    • Replication is efficient in many tumor cells, even those with wild-type p53.
    • In tumor cells, ONYX-015 fails to induce active p53 due to a disrupted E1A-p53 pathway linked to p14ARF loss.
    • Elevated Mdm2 activity (from p14ARF loss or activated Ras) prevents functional p53 accumulation during infection.

    Conclusions:

    • The E1B 55K deletion in ONYX-015 leads to differential replication based on host cell p53 pathway status.
    • Loss of p14ARF and subsequent Mdm2 hyperactivity are key mechanisms allowing ONYX-015 to evade p53-mediated suppression in tumor cells.
    • These findings highlight the importance of the p53 pathway in determining the efficacy of oncolytic adenoviruses like ONYX-015.