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Recent advances in HER2-targeted inhibitors for cancer therapy
1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
Abstract:
HER2 (ErbB2), a ligand-independent HER family member, regulates cell growth, differentiation, and survival. Its overexpression, gene amplification, and activating mutations are oncogenic drivers in multiple malignancies. The past two decades have witnessed transformative advances in HER2-targeted therapeutics, exemplified by tyrosine kinase inhibitors (TKIs), including first-generation reversible pan-HER (e.g., lapatinib), second-generation covalent pan-HER (neratinib, pyrotinib), and novel selective HER2 inhibitors (tucatinib, sevabertinib, zongertinib). Nonetheless, the extensive molecular heterogeneity in HER2 activation (e.g., dimerization, amplification) and mutation profiles (e.g., L755S, exon 20 insertions), combined with tumor-type-specific pathogenic mechanisms, poses significant challenges to precision oncology in clinical practice. Currently, numerous promising inhibitors in preclinical and clinical development hold potential for providing more effective treatment options. This review comprehensively summarizes recent advances in HER2-targeted TKIs and their emergent resistance mechanisms, further analyzing strategies to both mitigate off-target toxicity and overcome resistance through rational design of selective HER2 inhibitors. Collectively, these insights provide a roadmap for developing next-generation precision therapies in HER2-driven cancers.
Insights
HER2-targeted therapies, including tyrosine kinase inhibitors (TKIs), show promise for cancer treatment. This review details advances in HER2 TKIs, resistance mechanisms, and strategies for next-generation precision therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Human Epidermal growth factor Receptor 2 (HER2/ErbB2) is a key regulator of cell processes, and its dysregulation drives various cancers.
- Overexpression, amplification, and mutations in HER2 are critical oncogenic drivers in numerous malignancies.
- Significant molecular heterogeneity in HER2 activation and mutation profiles presents challenges for precision oncology.
Purpose of the Study:
- To comprehensively review recent advancements in HER2-targeted tyrosine kinase inhibitors (TKIs).
- To analyze emergent resistance mechanisms to HER2-targeted therapies.
- To explore strategies for mitigating off-target toxicity and overcoming resistance through rational drug design.
Main Methods:
- Literature review of preclinical and clinical studies on HER2-targeted TKIs.
- Analysis of molecular heterogeneity in HER2 activation and mutation profiles.
- Examination of resistance mechanisms and strategies for next-generation inhibitors.
Main Results:
- The development of HER2-targeted TKIs has advanced significantly, with first-generation, second-generation, and novel selective inhibitors available.
- Molecular heterogeneity and resistance mechanisms pose challenges to current HER2-targeted treatments.
- Numerous promising inhibitors are in development, offering potential for improved therapeutic options.
Conclusions:
- Advances in HER2-targeted TKIs offer new hope for patients with HER2-driven cancers.
- Understanding and overcoming resistance mechanisms are crucial for enhancing treatment efficacy.
- Rational design of selective HER2 inhibitors is key to developing next-generation precision therapies.
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