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Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
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An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy

Cedric Darini1, Nour Ghaddar1,2, Catherine Chabot1

  • 1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.

Nature Communications
|May 16, 2019
PubMed

Insights

The PKR/eIF2α-P pathway fights HER2+ cancers. Stimulating this pathway with SAL003 enhances Trastuzumab effectiveness in resistant breast and gastric tumors, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Trastuzumab is a key treatment for HER2+ cancers, but resistance limits its efficacy.
  • The integrated stress response, regulated by phosphorylated eukaryotic initiation factor 2 alpha (eIF2α-P), influences cancer cell survival.
  • Understanding resistance mechanisms is crucial for improving HER2+ cancer therapy.

Purpose of the Study:

  • To investigate the anti-tumor role of the PKR/eIF2α-P pathway in HER2+ breast cancer.
  • To explore the potential of targeting this pathway to overcome Trastuzumab resistance.
  • To correlate eIF2α-P levels with patient response to Trastuzumab therapy.

Main Methods:

  • Utilized a mouse model of HER2+ breast cancer.
  • Examined the induction of the PKR/eIF2α-P pathway by Trastuzumab in sensitive and resistant tumors.
  • Assessed the effect of the phosphatase inhibitor SAL003 on Trastuzumab efficacy in resistant models.
  • Analyzed the prognostic value of eIF2α-P in HER2+ metastatic breast cancer patients.

Main Results:

  • Demonstrated an anti-tumor function for the PKR/eIF2α-P pathway, dependent on ATF4, P21CIP1, and JNK1/2.
  • Found that Trastuzumab induces the PKR/eIF2α-P pathway in sensitive, but not resistant, HER2+ tumors.
  • Showed that SAL003 enhances Trastuzumab potency in resistant HER2+ breast and gastric tumors.
  • Correlated higher eIF2α-P levels with improved patient response to Trastuzumab in metastatic breast cancer.

Conclusions:

  • The PKR/eIF2α-P pathway acts as a tumor suppressor in HER2+ cancers.
  • Pharmacological stimulation of eIF2α-P phosphorylation can overcome Trastuzumab resistance.
  • eIF2α-P is a potential biomarker for predicting Trastuzumab treatment response.

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