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Updated: Feb 14, 2026

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Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer

Na Zhao1,2,3, Jin Cao1,2,3, Longyong Xu1,2,3

  • 1Department of Molecular and Cellular Biology.

The Journal of Clinical Investigation
|February 27, 2018
PubMed

Insights

Oncogenic MYC drives breast cancer by activating the unfolded protein response (UPR) via the IRE1/XBP1 pathway. Inhibiting this pathway selectively kills MYC-driven cancer cells and enhances chemotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Homeostasis

Background:

  • The unfolded protein response (UPR) is crucial in cancer, influencing tumor progression and treatment resistance.
  • Mechanisms of UPR activation and regulation in cancer remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which oncogenic MYC regulates the IRE1/XBP1 branch of the UPR in breast cancer.
  • To investigate the therapeutic potential of targeting the IRE1/XBP1 pathway in MYC-driven cancers.

Main Methods:

  • Investigated MYC's regulation of IRE1 transcription via promoter and enhancer binding.
  • Analyzed MYC-XBP1 transcriptional complex formation and activity.
  • Assessed the synthetic lethality of XBP1 silencing in MYC-hyperactivated cells.
  • Evaluated the efficacy of IRE1 RNase inhibitor 8866 in preclinical cancer models and in combination with docetaxel.

Main Results:

  • MYC directly controls IRE1 transcription and enhances XBP1 transcriptional activity.
  • XBP1 acts as a synthetic lethal partner to MYC; its silencing selectively inhibits MYC-hyperactivated cell growth.
  • Pharmacological inhibition of IRE1 RNase activity with 8866 suppressed MYC-overexpressing tumor growth in vivo.
  • 8866 significantly potentiated docetaxel efficacy, leading to rapid tumor regression.

Conclusions:

  • Established a synthetic lethal interaction between the IRE1/XBP1 pathway and MYC hyperactivation.
  • Demonstrated that targeting the IRE1/XBP1 pathway is a promising therapeutic strategy for MYC-driven breast cancers.
Keywords:
Breast cancerCell stressDrug therapyOncologyTherapeutics

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