Baird Anne-Marie, Easty David, Jarzabek Monika, Shiels Liam, Soltermann Alex, Klebe Sonja, Raeppel Stéphane, MacDonagh Lauren, Wu Chengguang, Griggs Kim, Kirschner Michaela B, Stanfill Bryan, Nonaka Daisuke, Goparaju Chandra M, Murer Bruno, Fennell Dean A, O'Donnell Dearbhaile M, Barr Martin P, Mutti Luciano, Reid Glen, Finn Stephen, Cuffe Sinead, Pass Harvey I, Opitz Isabelle, Byrne Annette T, O'Byrne Kenneth J, Gray Steven G
Thoracic Oncology Research Group, Labmed Directorate, St. James's Hospital, Dublin, Ireland.
Cancer and Ageing Research Program, Queensland University of Technology, Brisbane, QLD, Australia.
Front Endocrinol (Lausanne). 2019 Feb 26;10:89. doi: 10.3389/fendo.2019.00089. eCollection 2019.
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy , however BMS-777607 was far superior to LCRF-0004. The and data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.
恶性胸膜间皮瘤（MPM）是一种侵袭性炎症性癌症，生存率很低。治疗选择充其量有限，且耐药性很常见。因此，迫切需要在这种疾病中确定新的治疗靶点，以改善患者的预后和生存时间。MST1R（RON）是一种跨膜受体酪氨酸激酶（RTK），是c-MET原癌基因家族的一部分。唯一被认为与MST1R（RON）结合的配体是巨噬细胞刺激因子1（MST1），也称为巨噬细胞刺激蛋白（MSP）或肝细胞生长因子样蛋白（HGFL）。在本研究中，我们证明MST1-MST1R（RON）信号轴在MPM中具有活性。用小分子抑制剂LCRF-0004靶向该通路，导致增殖减少，同时凋亡增加。细胞周期进程也受到影响。重组MST1治疗在增殖或凋亡方面均无法克服LCRF-0004的作用。随后，另一种小分子抑制剂BMS-777607（靶向MST1R（RON）、MET、Tyro3和Axl）的作用也导致MPM细胞的增殖能力下降。在一组MPM患者样本中，免疫组化检测显示总MST1R高阳性是预后良好的独立预测指标。此外，MST1表达水平升高也与更好的生存率相关。本研究还确定了LCRF-0004和BMS-777607在MPM异种移植模型中的疗效。LCRF-0004和BMS-777607均显示出显著的抗肿瘤疗效，然而BMS-777607远优于LCRF-0004。本研究产生的数据表明，与单独靶向MST1R相比，靶向MST1R/MET/TAM信号通路的多靶点酪氨酸激酶抑制剂（multi-TKI）可能为MPM的治疗提供更有效的治疗策略。
