The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins
التفاصيل البيبلوغرافية
العنوان:
The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins
// Liangshun You 1 , Hui Liu 1 , Jian Huang 2 , Wanzhuo Xie 1 , Jueying Wei 1 , Xiujin Ye 1 , Wenbin Qian 1 1 Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China 2 Department of Hematology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, P.R. China Correspondence to: Wenbin Qian, email: qianwenb@hotmail.com Keywords: BCR/ABL, T315I mutation, chronic myeloid leukemia, JNJ-26854165 Received: May 14, 2016 Accepted: December 05, 2016 Published: December 15, 2016 ABSTRACT Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant. The response to JNJ-26854165 is associated with the downregulation of BCR/ABL dependently of proteosome activation. Moreover, in all tested CML cells, with the exception of T315I mutation cells, combining JNJ-26854165 and tyrosine kinase inhibitor (TKI) Imatinib or PD180970 leads to a synergistic effect. In conclusion, our results suggest that JNJ-26854165, used either alone or in combination with TKIs, represents a promising novel targeted approach to overcome TKI resistance and improve patient outcome in CML.
