von Hessert-Vaudoncourt Claus, Lelek Sara, Geisler Christina, Hartung Teresa, Bröker Vanessa, Briest Franziska, Mochmann Liliana, Jost-Brinkmann Fabian, Sedding Dagmar, Benecke Joana, Freitag Helma, Wolfshöfer Sebastian, Lammert Hedwig, Nölting Svenja, Hummel Michael, Schrader Jörg, Grabowski Patricia
Medical Clinic III, Hematology, Oncology, Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Front Pharmacol. 2024 Feb 5;15:1308686. doi: 10.3389/fphar.2024.1308686. eCollection 2024.
Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed. We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide. BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression. SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone. We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.
生长抑素类似物（SSAs）常用于治疗神经内分泌肿瘤（NETs）中的激素分泌过多，但它们抑制增殖的程度备受争议。我们研究了新型SSA兰瑞肽对支气管肺神经内分泌肿瘤（BP-NETs）的抗增殖作用。我们重点评估了用磷脂酰肌醇3-激酶（PI3K）抑制剂和雷帕霉素哺乳动物靶点（mTOR）抑制剂预处理细胞是否能增强兰瑞肽的抗增殖作用。用PI3K抑制剂BYL719（阿培利司）、mTOR抑制剂依维莫司和SSA兰瑞肽处理BP-NET细胞系NCI-H720和NCI-H727，以确定对NET分化标志物、细胞存活、增殖以及癌症相关通路改变的影响。先前报道天然表达生长抑素受体（SSTRs）的NT-3细胞用作SSTR表达的对照。用BYL719处理后，NCI-H720和NT-3细胞中的SSTR2上调。此外，在NCI-H720和NCI-H727中测试的由BYL719、依维莫司加兰瑞肽组成的联合治疗导致细胞增殖以剂量依赖方式减少。还诱导了激活细胞死亡机制的蛋白质产生。值得注意的是，对NCI-H720进行的多重基因表达分析表明，BYL719加兰瑞肽对有丝分裂原下调的作用比单独使用兰瑞肽更强。我们报告了对BP-NET细胞系在基因/蛋白质表达水平上因兰瑞肽与由BYL719和依维莫司组成的预处理联合使用而发生变化的广泛分析。有趣的是，SSTR表达的重新诱导可用于治疗和诊断应用。本研究的总体结果支持在临床前研究中评估使用兰瑞肽的联合疗法，以进一步增强其抗增殖作用，并最终促进其在高级别肿瘤中的应用。
