Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells

// Jianyun Zhao 1, 6 , Xiaojia Niu 1 , Xinyu Li 1 , Holly Edwards 2, 3 , Guan Wang 1 , Yue Wang 4 , Jeffrey W Taub 5, 6 , Hai Lin 7 , Yubin Ge 2, 3 1 National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China 2 Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA 3 Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 4 Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China 5 Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA 6 Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA 7 Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China Correspondence to: Yubin Ge, email: gey@karmanos.org Hai Lin, email: maillinhai@sina.com Jeffrey W Taub, email: jtaub@med.wayne.edu Keywords: LY2603618, ABT-199, acute myeloid leukemia, CHK1, Mcl-1 Received: February 29, 2016 Accepted: April 16, 2016 Published: May 05, 2016 ABSTRACT Resistance to standard chemotherapy agents remains a major obstacle for improving treatment outcomes for acute myeloid leukemia (AML). The Bcl-2-selective inhibitor ABT-199 has demonstrated encouraging preclinical results, drug resistance remains a concern. Mcl-1 has been demonstrated to contribute to ABT-199 resistance, thus combining with therapies that target Mcl-1 could overcome such resistance. In this study, we utilized a CHK1 inhibitor, LY2603618, to decrease Mcl-1 and enhance ABT-199 efficacy. We found that LY2603618 treatment resulted in abolishment of the G2/M cell cycle checkpoint and increased DNA damage, which was partially dependent on CDK activity. LY2603618 treatment resulted in decrease of Mcl-1, which coincided with the initiation of apoptosis. Overexpression of Mcl-1 in AML cells significantly attenuated apoptosis induced by LY2603618, confirming the critical role of Mcl-1 in apoptosis induced by the agent. Simultaneous treatment with LY2603618 and ABT-199 resulted in synergistic induction of apoptosis in both AML cell lines and primary patient samples. Our findings provide new insights into overcoming a mechanism of intrinsic ABT-199 resistance in AML cells and support the clinical development of combined ABT-199 and CHK1 inhibition.