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Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative

Aiindrila Dhara1,2, Imlimaong Aier3, Souhadri Das1

  • 1Department of Biological Sciences, Bose Institute, Kolkata, West Bengal, India.

NPJ Breast Cancer
|October 28, 2025
PubMed

Insights

Triple Negative Breast Cancer (TNBC) drug resistance is driven by ETS1 protein stability, enhanced by DNAPKcs phosphorylation. Targeting DNAPKcs with inhibitors degrades ETS1, promoting apoptosis in resistant TNBC cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Triple Negative Breast Cancer (TNBC) presents a significant clinical challenge due to high rates of chemoresistance and metastasis.
  • While ETS1 overexpression correlates with TNBC aggressiveness, its precise role in therapeutic relapse remains unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which ETS1 contributes to acquired chemoresistance in Triple Negative Breast Cancer.
  • To investigate the role of DNAPKcs in regulating ETS1 stability and function in drug-resistant TNBC.

Main Methods:

  • Utilized TNBC cell line models with acquired resistance to 5'-Fluorouracil and doxorubicin.
  • Investigated the effect of DNAPKcs-mediated phosphorylation on ETS1 stability and degradation.
  • Performed transcriptomic profiling of resistant cells and patient samples.
  • Assessed the efficacy of DNAPKcs inhibitors in vitro.

Main Results:

  • ETS1 was identified as a key driver of acquired drug resistance in TNBC models.
  • DNAPKcs-mediated phosphorylation of ETS1 at Serine 251 enhances its stability, promoting resistance.
  • Phosphorylated ETS1 activates E2F, MYC, and G2/M pathways, increasing DNA synthesis and proliferation.
  • DNAPKcs inhibitors led to ETS1 degradation, suppressed proliferation, and induced apoptosis in resistant cells.
  • Elevated phospho-S251 ETS1 and ETS1-driven proliferative signatures were found in drug-resistant TNBC patients.

Conclusions:

  • DNAPKcs-mediated ETS1 phosphorylation is a critical mechanism promoting chemoresistance in TNBC.
  • Targeting DNAPKcs kinase presents a potential therapeutic strategy to overcome drug resistance in TNBC.
  • Phospho-S251 ETS1 and associated gene signatures may serve as biomarkers for therapeutic response in TNBC.

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