論文 - 詳細
| RRC ID | 83565 |
|---|---|
| 著者 | Wang H, Yuan S, Zheng Q, Zhang S, Zhang Q, Ji S, Wang W, Cao Y, Guo Y, Yang X, Geng H, Yang F, Xi S, Jin G, Zhang J, Gao Q, Bernards R, Qin W, Wang C. |
| タイトル | Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs. |
| ジャーナル | Gastroenterology |
| Abstract |
BACKGROUND & AIMS:Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. METHODS:A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. RESULTS:The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. CONCLUSIONS:Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy. |
| 巻・号 | 166(6) |
| ページ | 1130-1144.e8 |
| 公開日 | 2024-6-1 |
| DOI | 10.1053/j.gastro.2024.01.025 |
| PII | S0016-5085(24)00062-3 |
| PMID | 38262581 |
| MeSH | Adaptor Proteins, Signal Transducing* / antagonists & inhibitors Adaptor Proteins, Signal Transducing* / metabolism Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology Cell Line, Tumor Cellular Senescence* / drug effects Cyclin-Dependent Kinase 4* / antagonists & inhibitors Cyclin-Dependent Kinase 4* / metabolism Cyclin-Dependent Kinase 6* / antagonists & inhibitors Cyclin-Dependent Kinase 6* / metabolism Drug Synergism Exportin 1 Protein* Hep G2 Cells Humans Hydrazines / pharmacology Hydrazines / therapeutic use Karyopherins* / antagonists & inhibitors Karyopherins* / metabolism Liver Neoplasms* / drug therapy Liver Neoplasms* / metabolism Liver Neoplasms* / pathology Mice Piperazines Protein Kinase Inhibitors* / pharmacology Proteolysis / drug effects Pyridines Receptors, Cytoplasmic and Nuclear* / antagonists & inhibitors Receptors, Cytoplasmic and Nuclear* / metabolism Retinoblastoma Binding Proteins / genetics Retinoblastoma Binding Proteins / metabolism Senotherapeutics / pharmacology Signal Transduction / drug effects Triazoles Ubiquitin-Protein Ligases* / metabolism Xenograft Model Antitumor Assays |
| IF | 17.373 |
| リソース情報 | |
| ヒト・動物細胞 | Huh7(RCB1366) Huh6(RCB1367) |