T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells
T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells
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DOI：
10.1038/s41416-020-0751-8
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发表时间：
2020-02-17
影响因子：
8.8
通讯作者：
Utikal, Jochen
中科院分区：
文献类型：
--
作者：
Granados, Karol;Hueser, Laura;Utikal, Jochen
背景耐药性仍然是黑色素瘤治疗的主要挑战之一。众所周知，肿瘤细胞在黑色素瘤进展期间经历表型转换，增加黑色素瘤可塑性和对丝裂原活化蛋白激酶抑制剂（MAPKi）的抗性。方法我们使用部分重编程模型研究黑色素瘤表型转换，以去分化小鼠黑色素瘤细胞和针对MAPKi的靶向黑色素瘤治疗适应。结果在这里，我们发现部分重编程的细胞是一个增殖性较低和去分化的细胞群体，表达干细胞的基因签名和抑制黑素细胞特异性标记。为了研究对MAPKi的适应，将细胞暴露于B-Raf原癌基因（BRAF）和促分裂原活化蛋白激酶激酶（MEK）抑制剂。去分化的细胞变得对MAPKi不太敏感，显示出细胞活力增加和细胞凋亡减少。此外，T-型钙通道的表达增加，在适应性鼠细胞和人类适应性黑色素瘤细胞。在体外和体内，用钙通道阻断剂米贝拉地尔处理诱导细胞死亡、分化和对MAPKi的敏感性。结论总之，我们发现黑色素瘤细胞的部分重编程诱导去分化和对MAPKi的适应。此外，我们假设钙通道阻滞剂，如米贝拉地尔，作为一个潜在的候选人，以恢复敏感性MAPKi在适应性黑色素瘤细胞。
Background Drug resistance remains as one of the major challenges in melanoma therapy. It is well known that tumour cells undergo phenotypic switching during melanoma progression, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). Methods We investigated the melanoma phenotype switching using a partial reprogramming model to de-differentiate murine melanoma cells and target melanoma therapy adaptation against MAPKi. Results Here, we show that partially reprogrammed cells are a less proliferative and more de-differentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate adaptation to MAPKi, cells were exposed to B-Raf Proto-Oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. De-differentiated cells became less sensitive to MAPKi, showed increased cell viability and decreased apoptosis. Furthermore, T-type calcium channels expression increased in adaptive murine cells and in human adaptive melanoma cells. Treatment with the calcium channel blocker mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo. Conclusion In summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. Moreover, we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells.