| Autor: |
Shaban N; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia., Kamashev D; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.; Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Emelianova A; World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov First Moscow State Medical University, Moscow 119991, Russia., Buzdin A; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.; Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia.; PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium. |
| Abstrakt: |
Members of the EGFR family of tyrosine kinase receptors are major regulators of cellular proliferation, differentiation, and survival. In humans, abnormal activation of EGFR is associated with the development and progression of many cancer types, which makes it an attractive target for molecular-guided therapy. Two classes of EGFR-targeted cancer therapeutics include monoclonal antibodies (mAbs), which bind to the extracellular domain of EGFR, and tyrosine kinase inhibitors (TKIs), which mostly target the intracellular part of EGFR and inhibit its activity in molecular signaling. While EGFR-specific mAbs and three generations of TKIs have demonstrated clinical efficacy in various settings, molecular evolution of tumors leads to apparent and sometimes inevitable resistance to current therapeutics, which highlights the need for deeper research in this field. Here, we tried to provide a comprehensive and systematic overview of the rationale, molecular mechanisms, and clinical significance of the current EGFR-targeting drugs, highlighting potential candidate molecules in development. We summarized the underlying mechanisms of resistance and available personalized predictive approaches that may lead to improved efficacy of EGFR-targeted therapies. We also discuss recent developments and the use of specific therapeutic strategies, such as multi-targeting agents and combination therapies, for overcoming cancer resistance to EGFR-specific drugs. |
