表觀遺傳藥物trischostatin A與LBH589增加抗藥性MV4-11白血病細胞株對cabozantinib的感受性

Epigenetic drugs trichostatin A and LBH589 increase the sensitivity of drug-resistant MV4-11 leukemia cell line to cabozantinib

大約20%~30%的急性骨髓性白血病（AML）患者具有FLT3基因突變，而酪胺酸激酶抑制劑，如midostaurin、quizartinib、gilteritinib等是FDA核准的治療用藥。然而，這種治療常常由於抗藥性的產生而失敗。我們先前建立了cabozantinib抗藥性的MV4-11白血病細胞株（MV4-11-XR），該細胞株也對FDA核准的quizartinib和sorafenib具有抗藥性；因此，該細胞株可用於研究抗藥性機制並開發替代治療策略。眾所周知，除了基因突變外，表觀遺傳調控異常在AML患者中也很常見。在本研究中，我們使用SCREEN-WELL®表觀遺傳學藥庫BML-2836篩選出廣泛的組蛋白去乙醯化酶抑制劑trichostatin A （TSA）和LBH589。隨後的實驗證明這兩種化合物對MV4-11和MV4-11-XR白血病細胞有效，包括抑制癌細胞生長和促進細胞凋亡。此外，分別以50 nM TSA或2 nM LBH589可以增加MV4-11-XR細胞株對cabozantinib的敏感性，從而將對cabozantinib的IC50降低至人類血漿濃度內。此結果可做為未來評估相關藥物臨床試驗時的重要參考。

About 20 to 30% of patients with acute myeloid leukemias (AML) have FLT3 gene mutations, for which tyrosine kinase inhibitors (TKIs) such as midostaurin, quizartinib, and gilteritinib have been approved by the FDA. However, this treatment often fails due to the development of drug resistance. We previously established a cabozantinib-resistant MV4-11 leukemia cells (MV4-11-XR), which also exhibits resistance to FDA-approved quizartinib and sorafenib; therefore, this cell line could be used to study the mechanism of drug resistance and to develop alternative treatment strategies. It is known that in addition to gene mutations, epigenetic regulatory abnormalities are also prevalent in patients with AML. In this study, we used SCREEN-WELL®Epigenetics library (BML-2836) to screen out two broad histone deacetylase inhibitors, trichostatin A (TSA) and LBH589, had potential to overcome the resistance. Subsequent experiments demonstrated that these two compounds were effective against MV4-11 and MV4-11-XR leukemia cells, including inhibiting cell growth and promoting cell apoptosis. Additionally, treatment with 50 nM TSA or 2 nM LBH589 increased the sensitivity of MV4-11-XR cells to cabozantinib, reducing its IC50 to within clinically achievable plasma concentrations. This result serves as an important reference for future clinical evaluation of related therapeutic agents.