褪黑激素可增强奈拉替尼治疗效果
虽然人类表皮生长因子受体HER2靶向治疗已经取得巨大成功，但是很大一部分HER2阳性乳腺癌仍然难免复发，如何提高现有HER2靶向药物的治疗效果仍然是亟待解决的临床难题。完全阻断HER2蛋白本身和HER2信号网络，对于实现有效的HER2靶向治疗至关重要。
2021年9月23日，英国《自然》旗下《肿瘤基因》在线发表大连医科大学附属第二医院的研究报告，发现褪黑激素通过促进HER2被内吞并被溶酶体降解，可增强HER1、HER2、HER4酪氨酸激酶抑制剂奈拉替尼对HER2阳性乳腺癌细胞的毒性作用。
褪黑激素是人类和哺乳动物上丘脑松果体分泌的天然激素，通过不同的作用机制可表现出抗肿瘤特性。该研究揭示了褪黑激素对破坏HER2蛋白从而减少HER2信号传导的作用。根据机制分析，褪黑激素可削弱热休克蛋白HSP90分子伴侣复合物对HER2的保护作用，触发HER2泛素化及其随后被内吞并被溶酶体降解。
褪黑激素对HER2信号传导的抑制作用可显著增强奈拉替尼对HER2阳性乳腺癌细胞的毒性作用。最后，该研究证实通过褪黑激素联合奈拉替尼对HER2的双重抑制可有效阻止体内HER2阳性乳腺肿瘤异种移植物的生长。
因此，该研究结果表明，褪黑激素＋奈拉替尼有望成为治疗HER2阳性乳腺癌的HER2双重阻断新策略。
相关链接
Oncogene. 2021 Sep 23. Online ahead of print.
Melatonin potentiates the cytotoxic effect of Neratinib in HER2+ breast cancer through promoting endocytosis and lysosomal degradation of HER2.
Liu Z, Sang X, Wang M, Liu Y, Liu J, Wang X, Liu P, Cheng H.
The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
Complete blockade of the HER2 protein itself and HER signaling network is critical to achieving effective HER2-targeted therapies. Despite the success of HER2-targeted therapies, the diseases will relapse in a significant fraction of patients with HER2+ breast cancers. How to improve the therapeutic efficacy of existing HER2-targeted agents remains an unmet clinical need. Here, we uncover a role of Melatonin in diminishing HER2-mediated signaling by destruction of HER2 protein. Mechanistically, Melatonin treatment attenuated the protective effect of the HSP90 chaperone complex on its client protein HER2, triggering ubiquitylation and subsequent endocytic lysosomal degradation of HER2. The inhibitory effect of Melatonin on HER2 signaling substantially enhanced the cytotoxic effects of the pan-HER inhibitor Neratinib in HER2+ breast cancer cells. Lastly, we demonstrate that dual inhibition of HER2 by combined use of Melatonin and Neratinib effectively blocked the growth of HER2+ breast tumor xenografts in vivo. Our findings shed light on the potential use of Melatonin in a novel dual HER2 blockade strategy for HER2+ breast cancer treatment.
PMID: 34556812
DOI: 10.1038/s41388-021-02015-w