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Pharmacological modulation of ATF6: exploiting a stress-integrative node to overcome drug resistance

Saeid Ghavami1, Mahmood Aghaei1, Saeid Ghavami2

  • 1Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.

Drug Discovery Today
|July 9, 2026
PubMed

Insights

Activating transcription factor 6 (ATF6) regulates cellular adaptation and is implicated in cancer progression. Inhibiting ATF6 may pose safety risks, necessitating careful therapeutic strategies.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR), impacting proteostasis, redox balance, and metabolism.
  • Aberrant ATF6 signaling in cancer drives proliferation, chemoresistance, ferroptosis evasion, and maintains genome stability.
  • Loss-of-function mutations in human ATF6 cause a syndrome affecting vision and hearing, indicating potential systemic toxicity of ATF6 inhibition.

Purpose of the Study:

  • To review ATF6 activation mechanisms and its role in cellular adaptation and cancer.
  • To explore the crosstalk between ATF6, autophagy, and apoptosis.
  • To discuss pharmacological strategies and combination therapies targeting ATF6 in cancer.

Main Methods:

  • Literature review of ATF6 activation pathways.
  • Analysis of ATF6's role in cancer hallmarks.
  • Examination of therapeutic interventions and combination strategies.

Main Results:

  • ATF6 integrates diverse cellular processes including adaptation, metabolism, and stress responses.
  • Dysregulated ATF6 signaling contributes to multiple cancer-associated phenotypes.
  • Potential safety concerns exist for systemic ATF6 inhibition due to its physiological roles.

Conclusions:

  • ATF6 is a critical regulator with dual roles in cellular homeostasis and cancer.
  • Understanding ATF6 activation and its interactions is crucial for developing effective cancer therapies.
  • Combination therapies targeting ATF6 should aim to maximize anti-cancer effects while minimizing physiological disruption.
Keywords:
ATF6ER stressautophagycancer progressioncombination therapydrug resistance

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