Qi Wenxiu, Zhang Wenbo, Edwards Holly, Chu Roland, Madlambayan Gerard J, Taub Jeffrey W, Wang Zhihong, Wang Yue, Li Chunhuai, Lin Hai, Ge Yubin
a National Engineering Laboratory for AIDS Vaccine; Key Laboratory for Molecular Enzymology and Engineering; the Ministry of Education; School of Life Sciences; Jilin University ; Changchun , China.
b Department of Oncology ; Wayne State University School of Medicine ; Detroit , MI USA.
Cancer Biol Ther. 2015;16(12):1784-93. doi: 10.1080/15384047.2015.1095406.
MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.
MK-1775是首个同类选择性Wee1抑制剂，已证实在多种恶性肿瘤中可与CHK1抑制剂协同作用。在本研究中，我们报告泛组蛋白去乙酰化酶抑制剂（HDACI）帕比司他在急性髓系白血病（AML）中与MK-1775协同作用，AML仍是一项临床挑战，需要更有效的治疗方法。使用AML细胞系模型和原发性患者样本，我们证明帕比司他和MK-1775协同诱导增殖停滞和细胞死亡。我们还证明帕比司他对初诊或复发患者来源的原发性AML原始细胞具有同等的抗白血病活性。有趣的是，单独使用帕比司他或与MK-1775联合治疗导致Wee1蛋白水平降低以及CHK1通路下调。CHK1的短发夹RNA（shRNA）敲低显著使AML细胞对MK-1775治疗敏感，而Wee1的敲低显著增强MK-1775和帕比司他诱导的细胞死亡。我们的结果表明，帕比司他在AML细胞中与MK-1775协同作用，至少部分是通过下调CHK1和/或Wee1，为AML联合治疗的临床开发提供了有力证据。
