論文 - 詳細
| RRC ID | 63734 |
|---|---|
| 著者 | Herbaux C, Kornauth C, Poulain S, Chong SJF, Collins MC, Valentin R, Hackett L, Tournilhac O, Lemonnier F, Dupuis J, Daniel A, Tomowiak C, Laribi K, Renaud L, Roos-Weil D, Rossi C, Van Den Neste E, Leyronnas C, Merabet F, Malfuson JV, Tiab M, Ysebaert L, Ng S, Morschhauser F, Staber PB, Davids MS. |
| タイトル | BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia. |
| ジャーナル | Blood |
| Abstract |
Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL) such as cytotoxic chemotherapy and alemtuzumab have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and TCR pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify novel combination therapy in this disease. Twenty-four primary T-PLL patient samples were studied using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis ('priming') and the relative dependence of a cell on different anti-apoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis, and predominantly depended on BCL-2 and MCL-1 for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated two patients with refractory T-PLL with the combination of venetoclax and ruxolitinib. We observed a deep response in the JAK3-mutated T-PLL and a stabilization of the unmutated disease. Our functional, precision medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting further exploration of such combinations clinically in T-PLL. |
| 巻・号 | 137(25) |
| ページ | 3495-3506 |
| 公開日 | 2021-6-24 |
| DOI | 10.1182/blood.2020007303 |
| PII | S0006-4971(21)00356-6 |
| PMID | 33598678 |
| MeSH | Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols / pharmacology* Bridged Bicyclo Compounds, Heterocyclic / pharmacology Female Humans Leukemia, Prolymphocytic, T-Cell / drug therapy* Leukemia, Prolymphocytic, T-Cell / metabolism Leukemia, Prolymphocytic, T-Cell / pathology MAP Kinase Signaling System / drug effects* Male Middle Aged Neoplasm Proteins* / antagonists & inhibitors Neoplasm Proteins* / metabolism Nitriles / pharmacology Pyrazoles / pharmacology Pyrimidines / pharmacology Sulfonamides / pharmacology |
| IF | 17.794 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | StromaNKtert(RCB2350) |