A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance

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Hussein Al-Akhrass1, James R W Conway2, Annemarie Svane Aavild Poulsen3

  • 1Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland. hussein.al-akhrass@utu.fi.

Oncogene
|January 9, 2021
PubMed

Insights

Resistance to HER2-targeted therapies in breast cancer involves HER3 signaling. This study reveals sortilin-related receptor (SorLA) stabilizes HER2-HER3 dimers, impacting therapy resistance and offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • HER2-targeted therapies are crucial for breast cancer treatment.
  • Therapy resistance often involves HER3 and HER2-HER3 dimers.
  • Understanding dimer regulation is key to overcoming resistance.

Purpose of the Study:

  • Investigate the relationship between HER2-HER3 signaling and SorLA.
  • Elucidate SorLA's role in HER2-HER3 dimer stability and signaling.
  • Determine SorLA's impact on anti-HER2 therapy resistance.

Main Methods:

  • Assessed SorLA transcription downstream of heregulin signaling.
  • Examined SorLA interaction with HER2-HER3 dimers.
  • Utilized cancer spheroids and zebrafish xenografts for in vitro and in vivo studies.

Main Results:

  • Heregulin signaling upregulates SorLA via MAPK pathway.
  • SorLA directly binds HER3, forming a trimeric complex with HER2.
  • SorLA inhibits lysosomal degradation of HER2-HER3 dimers in a Rab4-dependent manner.
  • SorLA loss reduces cell proliferation and sensitizes resistant cells to neratinib.

Conclusions:

  • SorLA plays a critical role in maintaining HER2-HER3 dimer stability.
  • SorLA inhibition represents a potential strategy to overcome anti-HER2 therapy resistance.
  • Targeting SorLA could re-sensitize metastatic breast cancer to neratinib.

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