不可逆的泛 HER 酪氨酸激酶抑制剂来那替尼 (neratinib) 被批准用于 HER2 阳性、早期和转移性乳腺癌 (BC) 患者。来那替尼相关腹泻是早期停药的最常见原因。临床前研究确定了来那替尼引起腹泻的机制以及预防和预防措施的基本原理。我们研究了来那替尼对大鼠肠道的影响，并对接受来那替尼治疗的 HER2 阳性 BC 患者进行了结肠发病机制的 2 期研究 (NCT04366713)。检查接受来那替尼或媒介物的雌性白化 Wistar 大鼠的结肠样本的组织病理学变化。 HER2 阳性 BC 患者每天接受一次 neratinib 240mg，持续长达 1 年。在基线和第 28 天收集结肠镜活检，以确定与大鼠病理学一致的变化。大鼠结肠的外观明显改变，具有相似的短路电流（Isc）以及对卡巴胆碱和毛喉素的反应。与对照治疗的动物相比，来那替尼治疗的动物中没有发现粘膜屏障丧失和/或分泌倾向显着增加。四名可进行终点评估的患者中有两名出现轻微的病理变化，与大鼠模型基本相似。临床前证据支持来那替尼引起的腹泻的炎症成分，而没有粘膜屏障功能丧失。 BC 患者的结肠镜检查结果表明，neratinib 治疗导致结肠轻度或无病理变化。© 2024 作者。生理报告由 Wiley periodicals LLC 代表生理学会和美国生理学会出版。

The irreversible pan-HER tyrosine kinase inhibitor neratinib is approved for patients with HER2-positive, early-stage and metastatic breast cancer (BC). Neratinib-associated diarrhea is the most common reason for early discontinuation. Preclinical studies identified mechanisms of neratinib-induced diarrhea and rationale for prophylactic and preventive measures. We studied effects of neratinib on rat intestines and conducted a phase 2 study of colon pathogenesis in patients with HER2-positive BC treated with neratinib (NCT04366713). Colon samples from female albino Wistar rats receiving neratinib or vehicle were examined for histopathological changes. Patients with HER2-positive BC received neratinib 240 mg once daily for up to 1 year. Colonoscopy biopsies were collected at baseline and at Day 28 to identify changes consistent with rat pathologies. Rat colons were markedly altered in appearance, with similar short circuit currents (Isc) and responses to carbachol and forskolin. Mucosal barrier loss and/or significant increase in secretory propensity in neratinib- versus control-treated animals were not seen. Two of four endpoint-evaluable patients presented with mild pathological changes, largely comparable with the rat model. Preclinical evidence supports an inflammatory component of neratinib-induced diarrhea without mucosal barrier function loss. Colonoscopy findings in patients with BC indicate mild or no pathological changes in the colon due to neratinib treatment.© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.