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Updated: Nov 20, 2025

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Sensitization of Cancers Resistant to HER2 Antibodies

Sagun Parakh1, Hui K Gan2, Andrew M Scott3

  • 1Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, Monash University, Melbourne, Australia; Department of Medical Oncology, Austin Hospital, Melbourne, Australia.

Critical Reviews in Oncogenesis
|January 19, 2021
PubMed

Insights

New therapies are emerging to overcome resistance to human epidermal growth factor receptor 2 (HER2) treatments in HER2-positive cancers. This review covers resistance mechanisms and novel therapeutic strategies for improved patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Human epidermal growth factor receptor 2 (HER2) oncogene addiction drives HER2-positive cancers.
  • Anti-HER2 therapies, like trastuzumab, have improved outcomes but face resistance.
  • Unmet need exists for therapies overcoming resistance and improving patient outcomes.

Purpose of the Study:

  • To review resistance mechanisms to approved HER2 antibodies.
  • To provide an overview of novel emerging anti-HER2 therapeutic agents.

Main Methods:

  • Literature review of established anti-HER2 therapies.
  • Analysis of known resistance mechanisms to HER2-targeted treatments.
  • Overview of novel therapeutic agents currently under development.

Main Results:

  • Resistance to HER2-targeted therapies is a significant clinical challenge.
  • Novel therapeutic strategies include antibody-drug conjugates, new antibodies, bispecific antibodies, and combinations with inhibitors (PI3K/mTOR, CDK4/6) and immunotherapy.
  • Emerging treatments show promise for HER2-high and HER2-low tumors.

Conclusions:

  • Understanding HER2 resistance mechanisms is crucial for developing effective treatments.
  • Novel therapeutic approaches offer potential to circumvent resistance and improve outcomes for patients with HER2-positive cancers.
  • Combination therapies and new drug modalities represent the future of HER2-targeted treatment.

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