Activation of the unfolded protein response bypasses trastuzumab-mediated inhibition of the PI-3K pathway

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Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
08:59

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

Published on: December 11, 2017

Sreekanth Kumandan1, Navin R Mahadevan, Kevin Chiu

  • 1The Laboratory of Immunology, Department of Medicine, Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0815, United States.

Cancer Letters
|December 4, 2012
PubMed

Insights

The unfolded protein response (UPR) can cause resistance to trastuzumab in HER2-positive breast cancer by reactivating growth signals and increasing Lipocalin 2 (LCN2) levels. Reducing UPR restores trastuzumab

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • HER2-positive breast cancer initially responds to trastuzumab.
  • Treatment resistance and cancer progression eventually occur.
  • The mechanisms underlying trastuzumab resistance are not fully understood.

Purpose of the Study:

  • To test the hypothesis that the unfolded protein response (UPR) can override HER2 inhibition by trastuzumab.
  • To investigate the role of UPR in reactivating growth signaling and Lipocalin 2 (LCN2) expression.
  • To explore potential therapeutic strategies targeting UPR in HER2-positive breast cancer.

Main Methods:

  • Utilized HER2-positive SKBr3 human breast cancer cells.
  • Administered trastuzumab and induced the unfolded protein response (UPR).
  • Measured Lipocalin 2 (LCN2) expression and secretion.
  • Used 4-phenyl butyric acid (PBA) to reduce UPR and PI3K/AKT pathway inhibitors.

Main Results:

  • Trastuzumab inhibited basal LCN2 expression.
  • UPR induction abrogated trastuzumab-mediated LCN2 downregulation and increased LCN2.
  • Reducing UPR with PBA restored trastuzumab's inhibitory effect on LCN2.
  • Inhibition of PI3K/AKT partially reduced LCN2 upregulation in UPR-induced cells.

Conclusions:

  • The unfolded protein response (UPR) may override trastuzumab inhibition in HER2-positive cancer cells.
  • UPR induction leads to increased LCN2 transcription and secretion, promoting cancer progression.
  • Targeting UPR presents a potential therapeutic strategy to overcome trastuzumab resistance.

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