Jin Xi-Feng, Spöttl Gerald, Maurer Julian, Nölting Svenja, Auernhammer Christoph Josef
Medizinische Klinik 4, LMU Klinikum, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany.
Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), LMU Klinikum, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany.
Cancers (Basel). 2021 Mar 23;13(6):1485. doi: 10.3390/cancers13061485.
This study assessed the antitumoral activity of the MEK inhibitor trametinib (TMT212) and the ERK1/2 inhibitor SCH772984, alone and in combination with the CDK4/6 inhibitor ribociclib (LEE011) in human neuroendocrine tumor (NET) cell lines in vitro.
Human NET cell lines BON1, QGP-1, and NCI-H727 were treated with trametinib or SCH772984, alone and in combination with ribociclib, to assess cell proliferation, cell cycle distribution, and protein signaling using cell proliferation, flow cytometry, and Western blot assays, respectively.
Trametinib and SCH772984, alone and in combination with ribociclib, significantly reduced NET cell viability and arrested NET cells at the G1 phase of the cell cycle in all three cell lines tested. In addition, trametinib also caused subG1 events and apoptotic PARP cleavage in QGP1 and NCI-H727 cells. A western blot analysis demonstrated the use of trametinib alone and trametinib in combination with ribociclib to decrease the expression of pERK, cMyc, Chk1, pChk2, pCDK1, CyclinD1, and c-myc in a time-dependent manner in NCI-H727 and QGP-1 cells.
MEK and ERK inhibition causes antiproliferative effects in human NET cell lines in vitro. The combination of the MEK inhibitor trametinib (TMT212) with the CDK4/6 inhibitor ribociclib (LEE011) causes additive antiproliferative effects. Future preclinical and clinical studies of MEK inhibition in NETs should be performed.
本研究评估了MEK抑制剂曲美替尼（TMT212）和ERK1/2抑制剂SCH772984单独及与CDK4/6抑制剂瑞博西尼（LEE011）联合应用于体外人神经内分泌肿瘤（NET）细胞系时的抗肿瘤活性。
分别使用细胞增殖、流式细胞术和蛋白质印迹分析，用曲美替尼或SCH772984单独及与瑞博西尼联合处理人NET细胞系BON1、QGP-1和NCI-H727，以评估细胞增殖、细胞周期分布和蛋白质信号传导。
曲美替尼和SCH772984单独及与瑞博西尼联合应用，在所有测试的三种细胞系中均显著降低了NET细胞活力，并使NET细胞停滞在细胞周期的G1期。此外，曲美替尼还在QGP1和NCI-H727细胞中引起亚G1期事件和凋亡性PARP裂解。蛋白质印迹分析表明，在NCI-H727和QGP-1细胞中，单独使用曲美替尼以及曲美替尼与瑞博西尼联合使用均能以时间依赖性方式降低pERK、cMyc、Chk1、pChk2、pCDK1、细胞周期蛋白D1和c-myc的表达。
MEK和ERK抑制在体外人NET细胞系中产生抗增殖作用。MEK抑制剂曲美替尼（TMT212）与CDK4/6抑制剂瑞博西尼（LEE011）联合应用产生相加的抗增殖作用。未来应开展NET中MEK抑制的临床前和临床研究。
