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

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.

IMMU-140, a Novel SN-38 Antibody–Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma

“…This is consistent with reports that in solid tumors, including melanoma, HLA-DR signaling is through phosphorylation of p125 focal adhesion kinase and not ERK (2,30). In AML, it has been suggested that increased expression of Bcl-2 proteins, in particular Mcl-1, act to attenuate apoptosis (35,36). Using drugs that induce DNA damage decreased levels of Mcl-1 and increased apoptosis in AML cells (36).…”

“…In AML, it has been suggested that increased expression of Bcl-2 proteins, in particular Mcl-1, act to attenuate apoptosis (35,36). Using drugs that induce DNA damage decreased levels of Mcl-1 and increased apoptosis in AML cells (36). Because IMMU-140 is capable of inducing significant damage to DNA in targeted cells through its SN-38 payload, including in AML, it is possible that an added benefit of IMMU-140 is to make targeted AML cells more sensitive to the direct signaling activity mediated by HLA-DR.…”

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

“…MOLM‐13 was purchased from AddexBio (San Diego, CA, USA). The cell lines were cultured as previously described, and were authenticated in August 2017 at the Genomics Core at Karmanos Cancer Institute using the PowerPlex ® 16 System from Promega (Madison, WI, USA). The cell lines were tested for the presence of mycoplasma by PCR on a monthly basis …”

“…MTT (3‐[4,5‐dimethyl‐thiazol‐2‐yl]‐2,5‐diphenyltetrazoliumbromide; Sigma‐Aldrich) assays were performed as previously described . Human PMNC samples were treated with variable concentrations of ABT‐199 and/or KPT‐330 for 72 hours.…”

The cell cycle checkpoint inhibitors in the treatment of leukemias

“…Zhao J. and colleagues have recently reported the efficacy of LY2603618 in combination with the BCL-2 inhibitor ABT-199 in AML cell lines and primary cells ( n  = 26). The authors demonstrated that the treatment with LY2606368 reduced the total amount of MCL-1 and, consequently, enhanced the efficacy of ABT-199 in terms of induction of apoptosis [101]. …”