Combination with γ-secretase inhibitor prolongs treatment efficacy of BRAF inhibitor in BRAF-mutated melanoma cells
Combination with γ-secretase inhibitor prolongs treatment efficacy of BRAF inhibitor in BRAF-mutated melanoma cells
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与γ-分泌酶抑制剂联合使用可延长 BRAF 抑制剂对 BRAF 突变黑色素瘤细胞的治疗效果
DOI：
10.1016/j.canlet.2016.03.028
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发表时间：
2016
期刊：
影响因子：
9.7
通讯作者：
David Schrama
中科院分区：
文献类型：
--
作者：
Guannan Zhu;Xiuli Yi;Sebastian Haferkamp;Sonja Hesbacher;Chunying Li;Matthias Goebeler;Tianwen Gao;Rol;Houben;David Schrama
黑素细胞中MAPK通路的致癌性触发导致衰老，衰老逃逸被认为是黑素细胞转化的一个关键步骤。在黑色素瘤中，BRAF抑制剂（BRAFi）在一部分治疗细胞中诱导衰老样状态-而不是杀死-有助于抑制肿瘤生长，但也可能提供复发的来源。在这里，我们证明了黑素细胞中的NOTCH激活不仅促进生长，而且还保护这些细胞免受癌基因诱导的衰老。反过来，用NOTCH激活酶γ-分泌酶抑制剂处理黑素瘤细胞导致诱导一部分细胞的衰老样状态，但总体上仅实现了对黑素瘤细胞生长的中度抑制。然而，γ-分泌酶抑制剂（GSI）与BRAFi的组合显著增加了治疗功效，特别是在长期培养中。此外，即使黑色素瘤细胞在连续BRAFi治疗后开始再生-患者BRAFi治疗的主要问题-仍然可能受到联合治疗的影响。因此，将GSI与BRAFi组合通过至少部分地延长经处理细胞的衰老样状态来增加治疗功效。
Oncogenic triggering of the MAPK pathway in melanocytes results in senescence, and senescence escape is considered as one critical step for melanocytic transformation. In melanoma, induction of a senescent-like state by BRAF-inhibitors (BRAFi) in a fraction of treated cells – instead of killing – contributes to the repression of tumor growth, but may also provide a source for relapse. Here, we demonstrate that NOTCH activation in melanocytes is not only growth-promoting but it also protects these cells against oncogene-induced senescence. In turn, treatment of melanoma cells with an inhibitor of the NOTCH-activating enzyme γ-secretase led to induction of a senescent-like status in a fraction of the cells but overall achieved only a moderate inhibition of melanoma cell growth. However, combination of γ-secretase inhibitor (GSI) with BRAFi markedly increased the treatment efficacy particularly in long-term culture. Moreover, even melanoma cells starting to regrow after continuous BRAFi treatment – the major problem of BRAFi therapy in patients – can still be affected by the combination treatment. Thus, combining GSI with BRAFi increases the therapeutic efficacy by, at least partially, prolonging the senescent-like state of treated cells.