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An Integrated Stress Response via PKR Suppresses HER2+ Cancers and Improves Trastuzumab Therapy

An Integrated Stress Response via PKR Suppresses HER2+ Cancers and Improves Trastuzumab Therapy

Cedric Darini, Nour Ghaddar, Catherine Chabot, Gloria Assaker, Siham Sabri, Shuo Wang, Jothilatha Krishnamoorthy, Marguerite Buchanan, Adriana Aguilar-Mahecha, Bassam Abdulkarim, Jean Deschenes, Jose Torres, etc.

Nat Commun. 2019 May 13;10(1):2139.

PMID: 31086176

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1164470534	Sal003		1164470-53-4	Price

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