BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma.
BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma.
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BET 蛋白抑制明显增强肝内胆管癌对 PI3K/mTOR 双重抑制的敏感性
DOI：
10.1038/s41419-021-04305-3
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发表时间：
2021-10-29
影响因子：
9
通讯作者：
Gong W
中科院分区：
文献类型：
--
作者：
Miao X;Liu C;Jiang Y;Wang Y;Kong D;Wu Z;Wang X;Tian R;Yu X;Zhu X;Gong W
肝内胆管细胞癌(ICC)是第二常见的原发性肝癌，是一种致命的恶性肿瘤，预后很差，治疗方案非常有限。尽管分子靶向治疗是一种很有前途的治疗策略，但不可避免地会出现对分子靶向治疗的耐药性，这是一项重大的临床挑战。在本研究中，我们证实哺乳动物靶标雷帕霉素(MTOR)信号通路是ICC中受影响最显著的通路。作为一种新型的磷脂酰肌醇3-激酶(PI3K)/mTOR双重抑制剂，BEZ235通过有效和特异地阻断PI3K/丝氨酸/苏氨酸激酶(AKT)/mTOR通路的异常激活而发挥抗肿瘤活性。我们通过流体动力将AKT和YAP载体导入小鼠肝脏，建立了原位ICC小鼠模型。我们的研究证实，BEZ235在体外可以抑制ICC细胞的增殖、侵袭和集落形成能力，但在体内不能有效地抑制ICC的进展。抑制PI3K/mTOR可通过抑制LATS1的磷酸化而上调c-Myc和YAP。这可能是一种新的介导PI3K/mTOR双抑制剂耐药的机制。然而，JQ1抑制BET可下调c-Myc和YAP的转录，从而增强PI3K/mTOR抑制剂的疗效。联合治疗的疗效结果表明，在体内外对ICC都有有效的治疗作用。我们的研究进一步证实了PI3K/mTOR双抑制剂和BET抑制通过调节巨噬细胞HIF-1α的表达而诱导巨噬细胞M1极化和抑制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。
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.
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