Thakur Varsha, Lu Jun, Roscilli Giuseppe, Aurisicchio Luigi, Cappelletti Manuela, Pavoni Emiliano, White William Lindsey, Bedogni Barbara
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
School of Science, Auckland University of Technology, New Zealand.
Oncotarget. 2017 Mar 14;8(11):17887-17896. doi: 10.18632/oncotarget.14437.
Melanoma remains one of the most aggressive and therapy-resistant cancers. Finding new treatments to improve patient outcomes is an ongoing effort. We previously demonstrated that melanoma relies on the activation of ERBB signaling, specifically of the ERBB3/ERBB2 cascade. Here we show that melanoma tumor growth is inhibited by 60% over controls when treated with lapatinib, a clinically approved inhibitor of ERBB2/EGFR. Importantly, tumor growth is further inhibited to 85% when the natural compound fucoidan from New Zealand U. pinnatifida is integrated into the treatment regimen. Fucoidan not only enhances tumor growth inhibition, it counteracts the morbidity associated with prolonged lapatinib treatment. Fucoidan doubles the cell killing capacity of lapatinib. These effects are associated with a further decrease in AKT and NFκB signaling, two key pathways involved in melanoma cell survival. Importantly, the enhancing cell killing effects of fucoidan can be recapitulated by inhibiting ERBB3 by either a specific shRNA or a novel, selective ERBB3 neutralizing antibody, reiterating the key roles played by this receptor in melanoma. We therefore propose the use of lapatinib or specific ERBB inhibitors, in combination with fucoidan as a new treatment of melanoma that potentiates the effects of the inhibitors while protecting from their potential side effects.
黑色素瘤仍然是最具侵袭性且对治疗耐药的癌症之一。寻找改善患者预后的新疗法是一项持续的工作。我们之前证明黑色素瘤依赖于ERBB信号通路的激活，特别是ERBB3/ERBB2级联反应。在此我们表明，用拉帕替尼（一种临床批准的ERBB2/EGFR抑制剂）治疗时，黑色素瘤肿瘤生长比对照组抑制了60%。重要的是，当将来自新西兰羽叶海带的天然化合物岩藻依聚糖纳入治疗方案时，肿瘤生长进一步被抑制至85%。岩藻依聚糖不仅增强了肿瘤生长抑制作用，还抵消了与长期拉帕替尼治疗相关的发病率。岩藻依聚糖使拉帕替尼的细胞杀伤能力加倍。这些效应与AKT和NFκB信号通路的进一步降低有关，这两条信号通路是参与黑色素瘤细胞存活的关键通路。重要的是，通过特异性短发夹RNA或新型选择性ERBB3中和抗体抑制ERBB3，可以重现岩藻依聚糖增强细胞杀伤的作用，这再次强调了该受体在黑色素瘤中所起的关键作用。因此，我们建议将拉帕替尼或特异性ERBB抑制剂与岩藻依聚糖联合使用，作为一种新的黑色素瘤治疗方法，这种方法既能增强抑制剂的效果，又能防止其潜在的副作用。
