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Synergistic Molecular Strategies for Targeting the Unfolded Protein Response in Cancer Therapy

Ovanes Muradyan1, Moudood Tahir1, Victoria Sarafian1,2

  • 1Department of Medical Biology, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria.

Pharmaceuticals (Basel, Switzerland)
|June 26, 2026
PubMed

Insights

Targeted synergistic therapies harness the Unfolded Protein Response (UPR) to combat cancer. By targeting endoplasmic reticulum stress, these therapies induce cancer cell death, overcoming resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • The Unfolded Protein Response (UPR) is crucial for maintaining cellular homeostasis, particularly in cancer cells with high secretory activity.
  • Cancer cells often exhibit hyperactivated UPR, making them dependent on this pathway for survival and vulnerable to endoplasmic reticulum (ER) stress.
  • Targeted therapies can modulate cellular pathways, including the UPR, offering new avenues for cancer treatment.

Purpose of the Study:

  • To establish a mechanistic framework for classifying synergistic cancer therapies based on their impact on ER stress and UPR activation.
  • To explore how different synergistic strategies influence the UPR's pro-survival and pro-apoptotic functions.
  • To identify therapeutic approaches that exploit cancer cell vulnerability to proteotoxic stress.

Main Methods:

  • Classification of synergistic therapies by their mechanisms of action, focusing on UPR modulation.
  • Analysis of agents targeting UPR feedback loops (e.g., GRP78 antagonists).
  • Investigation of inhibitors targeting key UPR branches (PERK, IRE1α) and indirect modulators (TKIs, BTK inhibitors).

Main Results:

  • Synergistic therapies can be categorized by their specific interactions with the ER stress and UPR pathways.
  • Pharmacologic agents can shift the UPR from a pro-survival to a pro-apoptotic state.
  • Combinations of therapies can exacerbate proteotoxic stress in cancer cells.

Conclusions:

  • Synergistic combinations of targeted therapies hold promise for overcoming therapeutic resistance in cancer.
  • These combinations can selectively induce apoptosis in cancer cells with high proteotoxic stress.
  • Targeting the UPR and ER stress represents a promising strategy in oncology.
Keywords:
ER stressUPRcancer cellsproteasome inhibitorssynergistic therapies

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