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<p>Human epidermal growth factor receptor 2 positive (HER2+) and estrogen receptor positive (ER+) breast cancer represents a distinct subtype characterized by complex receptor crosstalk, which can promote therapeutic resistance. Dual targeting of HER2 and ER has shown potential both pre-clinically and in patients. However, investigations of optimal drug combinations remain limited. The advent of novel small molecule therapies and next-generation hormonal treatments suggests the need for additional combinatorial studies. In this report, we demonstrate that combining the pan-HER tyrosine kinase inhibitor neratinib with next-generation, orally available selective estrogen receptor degraders (SERDs), particularly camizestrant, elicits potent synergistic anti-tumor effects in HER2+/ER+ pre-clinical models. Neratinib and camizestrant demonstrated strong synergy in vitro across multiple cell lines, including HER2-low and anti-HER2 therapy-resistant models. The combination showed the greatest induction of apoptosis and inhibition of 3D spheroid growth compared to single agents and other neratinib plus SERD combinations. Neratinib treatment alone induced compensatory increases in ER-associated gene expression, which were reversed by camizestrant co-treatment. In vivo, neratinib plus camizestrant resulted in significant tumor regression, with all treated mice showing tumor shrinkage and marked suppression of pro-tumorigenic signaling. These findings support the clinical evaluation of neratinib and camizestrant as a promising new strategy for patients with HER2+/ER+ breast cancer.</p>

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Combining orally available selective estrogen receptor degraders with pan-HER tyrosine kinase inhibitor neratinib in pre-clinical models of HER2+/ER+ breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

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  • Amira F. Mahdi,
  • Myra Castel,
  • Neil T. Conlon,
  • Debbie O’Reilly,
  • Niall Ashfield,
  • Alexander Caffrey,
  • Ailish Carey,
  • Neil A. O’Brien,
  • Enrique Guandique,
  • Georg F. Bischof,
  • John Crown,
  • Denis M. Collins

摘要

Human epidermal growth factor receptor 2 positive (HER2+) and estrogen receptor positive (ER+) breast cancer represents a distinct subtype characterized by complex receptor crosstalk, which can promote therapeutic resistance. Dual targeting of HER2 and ER has shown potential both pre-clinically and in patients. However, investigations of optimal drug combinations remain limited. The advent of novel small molecule therapies and next-generation hormonal treatments suggests the need for additional combinatorial studies. In this report, we demonstrate that combining the pan-HER tyrosine kinase inhibitor neratinib with next-generation, orally available selective estrogen receptor degraders (SERDs), particularly camizestrant, elicits potent synergistic anti-tumor effects in HER2+/ER+ pre-clinical models. Neratinib and camizestrant demonstrated strong synergy in vitro across multiple cell lines, including HER2-low and anti-HER2 therapy-resistant models. The combination showed the greatest induction of apoptosis and inhibition of 3D spheroid growth compared to single agents and other neratinib plus SERD combinations. Neratinib treatment alone induced compensatory increases in ER-associated gene expression, which were reversed by camizestrant co-treatment. In vivo, neratinib plus camizestrant resulted in significant tumor regression, with all treated mice showing tumor shrinkage and marked suppression of pro-tumorigenic signaling. These findings support the clinical evaluation of neratinib and camizestrant as a promising new strategy for patients with HER2+/ER+ breast cancer.