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An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy

Author

Listed:
  • Cedric Darini

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Nour Ghaddar

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

  • Catherine Chabot

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Gloria Assaker

    (McGill University
    Research Institute of McGill University Health Centre)

  • Siham Sabri

    (McGill University
    Research Institute of McGill University Health Centre)

  • Shuo Wang

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Jothilatha Krishnamoorthy

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Marguerite Buchanan

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Adriana Aguilar-Mahecha

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Bassam Abdulkarim

    (Research Institute of McGill University Health Centre
    McGill University)

  • Jean Deschenes

    (University of Alberta)

  • Jose Torres

    (McGill University)

  • Josie Ursini-Siegel

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

  • Mark Basik

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

  • Antonis E. Koromilas

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

Abstract

Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21CIP1 and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy.

Suggested Citation

  • Cedric Darini & Nour Ghaddar & Catherine Chabot & Gloria Assaker & Siham Sabri & Shuo Wang & Jothilatha Krishnamoorthy & Marguerite Buchanan & Adriana Aguilar-Mahecha & Bassam Abdulkarim & Jean Desche, 2019. "An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10138-8
    DOI: 10.1038/s41467-019-10138-8
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    Cited by:

    1. Yujie Zhu & Mingchao Zhang & Weiran Wang & Shuang Qu & Minghui Liu & Weiwei Rong & Wenwen Yang & Hongwei Liang & Caihong Zeng & Xiaodong Zhu & Limin Li & Zhihong Liu & Ke Zen, 2023. "Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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