BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma

• Published in: Cell death & disease 2021-10, Vol.12 (11), p.1020-1020, Article 1020
• Main Authors: Miao, Xiaolong, Liu, Chen, Jiang, Yuancong, Wang, Yao, Kong, Deqiang, Wu, Zelai, Wang, Xinyi, Tian, Rui, Yu, Xing, Zhu, Xuhang, Gong, Weihua
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 42/89; 631/67/1059/602; 631/67/70; 82/51; 96/1; 96/31; AKT protein; Animals; Antibodies; Antineoplastic Agents - administration & dosage; Azepines - administration & dosage; Bet protein; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Biochemistry; Biomedical and Life Sciences; c-Myc protein; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Disease Models, Animal; Drug Therapy, Combination - methods; Enzyme inhibitors; Humans; Hypoxia-inducible factor 1a; Imidazoles - administration & dosage; Immunology; Life Sciences; Liver cancer; Macrophages; Malignancy; Mice; MTOR Inhibitors - administration & dosage; Myc protein; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - administration & dosage; Phosphorylation; Plasmids; Polarization; Protein-serine/threonine kinase; Quinolines - administration & dosage; Rapamycin; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Signal Transduction - drug effects; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Transcription; Transcriptome; Transfection; Treatment Outcome; Triazoles - administration & dosage; Yes-associated protein
• ISSN: 2041-4889; 2041-4889
• 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.