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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
14:20

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

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Targeting Oncogenic HER2 Mutations by Neratinib-induced HER2 Ubiquitination and Degradation in Breast Cancer

Yingqiu Zhang1, Xuesong Meng1, Yueshun Hong1

  • 1Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, China.

Current Cancer Drug Targets
|July 28, 2026
PubMed
Abstract

Insights

Neratinib effectively targets drug-resistant HER2 mutations by promoting their degradation. This mechanism suppresses cancer cell growth and oncogenic signaling, offering a new therapeutic strategy for resistant HER2 mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Oncogenic HER2 mutations represent a tumorigenic mechanism independent of HER2 overexpression.
  • These mutations can confer resistance to existing HER2-targeted therapies.

Purpose of the Study:

  • To investigate the inhibitory effects of neratinib on drug-resistant oncogenic HER2 mutations.
  • To examine neratinib's mechanism of action against these resistant mutations, building on prior findings of neratinib promoting HER2 endocytic degradation.

Main Methods:

  • Immunofluorescence for HER2 intracellular distribution.
  • Western blotting for HER2, pAKT, and pMEK expression.
  • MTT, colony formation, and wound-healing assays for proliferation.
  • In vivo assessment of tumorigenic potential.
  • Immunoprecipitation and immunofluorescence for HER2 ubiquitination and localization.

Main Results:

  • HER2 mutations were found to enhance AKT/MEK signaling and promote tumorigenesis in vitro and in vivo.
  • Neratinib suppressed downstream signaling, growth, and spheroid formation in cells with HER2 mutants (T733I, L755S, exon 16 deletion).
  • Neratinib treatment led to enhanced ubiquitination and internalization of these HER2 mutants.

Conclusions:

  • Neratinib induces ubiquitination and degradation of HER2 mutants, suppressing oncogenic signaling.
  • This degradation mechanism explains neratinib's efficacy against therapy-resistant HER2 mutations.
  • Neratinib suppresses cancer cell growth by targeting drug-resistant HER2 mutations via endocytic degradation.
Keywords:
HER2breast cancerdrug resistanceneratiniboncogenic mutationubiquitination; endocytosis

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