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MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance

Dawid Mehlich1,2,3, Michał Łomiak1, Aleksandra Sobiborowicz4,5

  • 1Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Warsaw, Poland.

Cell Death & Disease
|November 28, 2021
PubMed

Insights

Mixed-Lineage Kinase 4 (MLK4) drives chemoresistance in triple-negative breast cancer (TNBC) by promoting DNA repair and survival pathways. Inhibiting MLK4 may resensitize TNBC to chemotherapy, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Triple-negative breast cancer (TNBC) presents significant treatment challenges due to chemoresistance.
  • Mixed-Lineage Kinase 4 (MLK4) is overexpressed in TNBC, correlating with aggressive tumor growth and metastasis.
  • The role of MLK4 in chemotherapy resistance in TNBC remains unexplored.

Purpose of the Study:

  • To investigate the functional role of MLK4 in chemoresistance in triple-negative breast cancer.
  • To determine if MLK4 influences the DNA damage response and survival pathways in TNBC cells.
  • To evaluate MLK4 as a potential therapeutic target for overcoming chemoresistance in TNBC.

Main Methods:

  • Utilized MLK4 knockdown and inhibition in TNBC cell lines and in vivo models.
  • Assessed sensitivity to chemotherapeutic agents (e.g., doxorubicin).
  • Investigated DNA damage accumulation, apoptosis, DNA repair pathways (non-homologous end-joining), and cytokine signaling (NF-кB) via phosphoproteomic profiling, reporter assays, and mRNA-seq.
  • Correlated MLK4 expression with patient survival data.

Main Results:

  • MLK4 knockdown or inhibition sensitized TNBC cells to chemotherapy in vitro and in vivo.
  • MLK4 deficiency led to persistent DNA damage and increased apoptosis upon chemotherapy treatment.
  • Loss of MLK4 reduced DNA damage response factor phosphorylation (ATM, CHK2) and impaired non-homologous end-joining repair.
  • MLK4 was essential for DNA damage-induced expression of NF-кB-associated survival cytokines.
  • High MLK4 expression correlated with poorer survival in TNBC patients receiving anthracycline chemotherapy.

Conclusions:

  • MLK4 plays a critical role in promoting chemoresistance in TNBC by regulating DNA damage response and survival signaling.
  • Targeting MLK4 represents a promising strategy to enhance the efficacy of chemotherapy and overcome treatment resistance in TNBC.
  • MLK4 inhibition could be a viable therapeutic approach for improving outcomes in patients with triple-negative breast cancer.

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