Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs.

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阿法替尼的作用机理和临床前发展

阿法替尼，与吉非替尼和厄洛替尼一起，被批准用于具有表皮生长因子受体（EGFR）活化突变的晚期非小细胞肺癌（NSCLC）的一线治疗。这是ErbB家族的不可逆抑制剂，作用于EGFR（HER1，ErbB1），ErbB2（HER2）和ErbB4（HER4）。共价结合至EGFR，HER2和ErbB4催化域中的半胱氨酸残基抑制了这些受体的酪氨酸激酶活性（TKIs），从而降低了ErbB二聚体之间的自磷酸化和转磷酸化作用，从而阻止了与生长和凋亡相关的下游信号通路的活性抑制。在临床前模型中，这导致了肿瘤大小的减小。此外，由于其作用机理，阿法替尼可能比第一代EGFR TKIs（吉非替尼和厄洛替尼）更有效，甚至可以克服对这种治疗的获得性耐药。最后，由于已证明与其他化疗药物和靶标药物具有协同作用，因此与其他药物联合使用可增强其临床开发。