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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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p53 Loss Mediates Hypersensitivity to ETS Transcription Factor Inhibition Based on PARylation-Mediated Cell Death

Carina Dinhof1,2, Christine Pirker1,2, Philipp Kroiss1,2

  • 1Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria.

Cancers
|November 4, 2020
PubMed

Insights

The study found that deleting the P53 gene sensitizes BRAF-mutated colon cancer cells to YK-4-279, an ETS factor inhibitor. This suggests ETS factor inhibition may treat therapy-resistant p53-null tumors with MAPK mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The E26 transformation-specific (ETS) factor inhibitor YK-4-279 targets ETS/EWS fusion-driven Ewing's sarcoma.
  • Understanding YK-4-279 responsiveness in ETS fusion-negative cancers is crucial for expanding therapeutic applications.

Purpose of the Study:

  • To identify molecular factors influencing YK-4-279 sensitivity in ETS fusion-negative cancers.
  • To investigate the role of P53 and BRAF mutations in YK-4-279 response.

Main Methods:

  • Cell viability screening in colon cancer models with and without P53 deletion and BRAF mutations.
  • Analysis of ETS1 expression at mRNA and protein levels.
  • Assessment of YK-4-279-induced DNA damage response (H2A.x phosphorylation) and cell death pathways (parthanatos).

Main Results:

  • P53 deletion significantly sensitized BRAF V600E-mutated RKO cells to YK-4-279, an effect less pronounced in BRAF wild-type HCT116 cells.
  • P53 deletion induced ETS1 overexpression under BRAF-mutated conditions, which was reversed by YK-4-279.
  • YK-4-279 induced parthanatos and DNA damage (H2A.x phosphorylation) more strongly in P53-null cells, with antagonistic effects observed with PARP or BRAF V600E inhibition.

Conclusions:

  • ETS factor inhibition is a potential therapeutic strategy for p53-null solid tumors harboring activating MAPK mutations.
  • The interplay between P53 status, BRAF mutation, and ETS1 expression dictates YK-4-279 sensitivity.
  • Targeting ETS factors offers a novel approach for treating therapy-resistant cancers.
Keywords:
ETS factor inhibitorETS1PARylationYK-4-279p53parthanatos

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