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Updated: Apr 26, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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A role for the pseudokinase HER3 in the acquired resistance against EGFR- and HER2-directed targeted therapy

Jeroen Claus1, Gargi Patel2, Tony Ng2

  • 1*Cancer Research UK, London Research Institute, Lincoln's Inn Fields, London WC2A 3LY, U.K.

Biochemical Society Transactions
|August 12, 2014
PubMed

Insights

Targeted cancer therapies like EGFR inhibitors are effective but resistance develops. The HER3 receptor and its ligand NRG are key mediators of this acquired resistance, and targeting HER3 is a promising strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeted therapies inhibiting the epidermal growth factor receptor (EGFR) family, including EGFR and HER2, are crucial in cancer treatment.
  • Acquired resistance to these targeted therapies is a significant clinical challenge, limiting their long-term efficacy.
  • Emerging research identifies HER3, a pseudokinase in the EGFR family, and its ligand neuregulin β1 (NRG) as critical players in resistance mechanisms.

Purpose of the Study:

  • To elucidate the roles of HER3 and NRG in mediating acquired resistance to EGFR-targeted cancer therapies.
  • To review current therapeutic strategies aimed at targeting HER3 to overcome treatment resistance.

Main Methods:

  • Literature review of recent studies on HER3 and NRG in cancer resistance.
  • Analysis of preclinical models and patient data implicating HER3 in resistance pathways.
  • Discussion of ongoing clinical efforts to develop HER3-targeted agents.

Main Results:

  • HER3 activation by NRG is a significant mechanism driving resistance to EGFR and HER2 inhibitors.
  • HER3 signaling contributes to tumor cell survival and proliferation despite targeted therapy.
  • Targeting HER3, either directly or indirectly, shows potential in overcoming acquired resistance.

Conclusions:

  • HER3 plays a pivotal role in the development of acquired resistance to EGFR-family targeted cancer therapies.
  • Developing strategies to inhibit HER3 signaling is essential for improving long-term patient outcomes.
  • Further research and clinical trials are warranted to validate HER3-targeted therapies for resistant cancers.

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