Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.
College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
Cell Death Dis. 2021 Oct 29;12(11):1020. doi: 10.1038/s41419-021-04305-3.
Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.
肝内胆管癌（ICC）是第二大常见的原发性肝癌，是一种致命的恶性肿瘤，预后差，治疗选择非常有限。尽管分子靶向治疗已成为一种有前途的治疗策略，但不可避免地会出现对分子靶向治疗的耐药性，这是一个主要的临床挑战。在这项研究中，我们证实哺乳动物雷帕霉素靶蛋白（mTOR）信号是 ICC 中受影响最显著的途径。作为一种新型的磷脂酰肌醇 3-激酶（PI3K）/mTOR 双重抑制剂，BEZ235 通过有效且特异性地阻断 PI3K/丝氨酸/苏氨酸激酶（AKT）/mTOR 通路的功能失调激活发挥抗肿瘤活性。我们通过将 AKT 和 yes 相关蛋白（YAP）质粒水动力转染到小鼠肝脏中，生成了原位 ICC 小鼠模型。我们的研究证实，BEZ235 可以抑制 ICC 细胞在体外的增殖、侵袭和集落形成能力，但不能有效抑制体内 ICC 的进展。PI3K/mTOR 的抑制允许通过抑制 LATS1 的磷酸化来上调 c-Myc 和 YAP。这将是一种介导对 PI3K/mTOR 双重抑制剂耐药的新机制。然而，Bromo 和末端结构域（BET）抑制剂 JQ1 通过下调 c-Myc 和 YAP 的转录来增强 PI3K/mTOR 抑制剂的疗效。联合治疗的疗效结果显示，体外和体内联合治疗对 ICC 均有效。我们的数据进一步证实，PI3K/mTOR 双重抑制剂和 BET 抑制的联合通过调节 HIF-1α 的表达，诱导巨噬细胞中 M1 极化并抑制 M2 极化。我们的研究为治疗原发性 ICC 提供了一种新的、有效的治疗策略。
