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ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation

Joao Nunes1, Hua Zhang1, Nicos Angelopoulos1

  • 1Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.

Oncotarget
|April 7, 2016
PubMed

Insights

Loss of autophagy related protein 9A (ATG9A) drives trastuzumab resistance in cancer cells by stabilizing Her2. Restoring ATG9A may overcome anti-Her2 therapy resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Trastuzumab resistance is a major clinical challenge in HER2-positive cancers.
  • Mechanisms of trastuzumab resistance, particularly acquired or de novo resistance, are not fully understood.

Purpose of the Study:

  • To investigate the proteomic changes associated with trastuzumab resistance.
  • To identify novel molecular targets for overcoming trastuzumab resistance.

Main Methods:

  • Stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics.
  • Comparative proteomic analysis of trastuzumab-sensitive and resistant cell lines (BT474, BT474-TR, JIMT1, MDA-453).
  • Functional assays including ectopic expression, gene silencing, and assessment of protein levels, phosphorylation, stability, and ubiquitination.

Main Results:

  • Autophagy related protein 9A (ATG9A) was identified as downregulated in trastuzumab-resistant cells.
  • Ectopic ATG9A expression reduced proliferation, Her2 protein levels, AKT phosphorylation, and Her2 stability in resistant cells.
  • ATG9A promoted c-Cbl recruitment to Her2, leading to increased Her2 polyubiquitination and lysosomal degradation.
  • Silencing c-Cbl abrogated ATG9A's effects and restored proliferation in resistant cells.

Conclusions:

  • Loss of ATG9A contributes to trastuzumab resistance by preventing Her2 lysosomal degradation.
  • ATG9A regulates Her2 stability and signaling through c-Cbl-mediated ubiquitination.
  • ATG9A represents a potential therapeutic target to overcome resistance to anti-HER2 therapies like trastuzumab.
Keywords:
ATG9ASILACbreast cancerresistancetrastuzumab

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