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Abstract：
BACKGROUND: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma.
METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy.
RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway.
CONCLUSIONS: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.
METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy.
RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway.
CONCLUSIONS: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.
摘要：
背景：黑色素瘤是最致命的皮肤癌，其特征是具有高转移潜力。在过去的十年里,靶向和免疫治疗为晚期和转移性黑色素瘤患者带来了革命性的生存益处，但这些治疗反应也是异质的和/或不能实现持久的反应。因此,改善预后的新型治疗策略仍未满足临床需求.这项研究的目的是评估RC48的治疗潜力和潜在的分子机制，RC48是一种新型的HER2靶抗体药物偶联物。无论是单独使用还是与dabrafenib合用,V600-突变型BRAF抑制剂，用于治疗晚期BRAF突变型皮肤黑色素瘤。
方法：我们评估了RC48单独或与dabrafenib联合使用的疗效，在BRAF突变型皮肤黑色素瘤细胞系和细胞衍生的异种移植（CDX）模型中。我们还进行了信号通路分析和全局mRNA测序，以探索联合治疗协同作用的潜在机制。
结果：我们的结果显示膜定位HER2在黑色素瘤细胞中的表达。RC48有效靶向并抑制HER2阳性人黑素瘤细胞系和相应CDX模型的生长。当使用RC48和dabrafenib时，在人BRAF突变体黑色素瘤细胞系和CDX模型中协同诱导肿瘤消退。机械上,我们的结果表明，联合疗法在体外诱导细胞凋亡和细胞周期阻滞，同时抑制细胞运动。此外，全球RNA测序分析表明，联合治疗导致几个关键信号通路的下调，包括PI3K-AKT通路，MAPK通路,AMPK通路,和FOXO途径。
结论：这些发现为联合使用抗HER2药物偶联物和BRAF抑制剂治疗BRAF突变型皮肤黑色素瘤奠定了临床前基础。
方法：我们评估了RC48单独或与dabrafenib联合使用的疗效，在BRAF突变型皮肤黑色素瘤细胞系和细胞衍生的异种移植（CDX）模型中。我们还进行了信号通路分析和全局mRNA测序，以探索联合治疗协同作用的潜在机制。
结果：我们的结果显示膜定位HER2在黑色素瘤细胞中的表达。RC48有效靶向并抑制HER2阳性人黑素瘤细胞系和相应CDX模型的生长。当使用RC48和dabrafenib时，在人BRAF突变体黑色素瘤细胞系和CDX模型中协同诱导肿瘤消退。机械上,我们的结果表明，联合疗法在体外诱导细胞凋亡和细胞周期阻滞，同时抑制细胞运动。此外，全球RNA测序分析表明，联合治疗导致几个关键信号通路的下调，包括PI3K-AKT通路，MAPK通路,AMPK通路,和FOXO途径。
结论：这些发现为联合使用抗HER2药物偶联物和BRAF抑制剂治疗BRAF突变型皮肤黑色素瘤奠定了临床前基础。
