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  3. Targeted dual degradation of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models

Targeted dual degradation of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models

  • Drug Resist Updat. 2024 Mar 13:74:101078. doi: 10.1016/j.drup.2024.101078.
Lu Yang 1,  Arup Bhattacharya 1,  Darrell Peterson 2,  Yun Li 1,  Xiaozhuo Liu 3,  Elisabetta Marangoni 4,  Valentina Robila 5,  Yuesheng Zhang 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
  • 2 Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, School of Pharmacy, Richmond, VA, USA.
  • 3 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 4 Translational Research Department, Institute of Curie, Paris, France.
  • 5 Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
  • 6 Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: [email protected].
PMID: 38503142 DOI: 10.1016/j.drup.2024.101078
Abstract

Aims: Human epidermal growth factor receptor 2 (HER2) is an oncogenic receptor tyrosine kinase amplified in approximately 20% of breast Cancer (BC). HER2-targeted therapies are the linchpin of treating HER2-positive BC. However, drug resistance is common, and the main resistance mechanism is unknown. We tested the hypothesis that drug resistance results mainly from inadequate or lack of inhibition of HER2 and its family member epidermal growth factor receptor (EGFR).

Methods: We used clinically relevant cell and tumor models to assess the impact of targeted degradation of HER2 and EGFR on trastuzumab resistance. Trastuzumab is the most common clinically used HER2 inhibitor. Targeted degradation of HER2 and EGFR was achieved using recombinant human protein PEPDG278D, which binds to the extracellular domains of the receptors. siRNA knockdown was used to assess the relative importance of EGFR and HER2 in trastuzumab resistance.

Results: Both HER2 and EGFR are overexpressed in all trastuzumab-resistant HER2-positive BC cell and tumor models and that all trastuzumab-resistant models are highly vulnerable to targeted degradation of HER2 and EGFR. Degradation of HER2 and EGFR induced by PEPDG278D causes extensive inhibition of oncogenic signaling in trastuzumab-resistant HER2-positive BC cells. This is accompanied by strong growth inhibition of cultured cells, orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of trastuzumab-resistant HER2-positive BC. siRNA knockdown indicates that eliminating both HER2 and EGFR is necessary to maximize therapeutic outcome.

Conclusions: This study unravels the therapeutic vulnerability of trastuzumab-resistant HER2-positive BC and shows that an agent that targets the degradation of both HER2 and EGFR is highly effective in overcoming drug resistance in this disease. The findings provide new insights and innovations for advancing treatment of drug-resistant HER2-positive breast Cancer that remains an unmet problem.

Keywords

EGFR; HER2; HER2 inhibitor; HER2-positive breast cancer; Prolidase; Receptor tyrosine kinase.

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