Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABL+ B-Lineage Acute Lymphoblastic Leukemia

Abstract

<b>Purpose:</b> BCR-ABL⁺ B-ALL leukemic cells are highly dependent on the expression of endogenous antiapoptotic MCL-1 to promote viability and are resistant to BH3-mimetic agents such as navitoclax (ABT-263) that target BCL-2, BCL-X_L, and BCL-W. However, the survival of most normal blood cells and other cell types is also dependent on <i>Mcl-1</i> Despite the requirement for MCL-1 in these cell types, initial reports of MCL-1-specific BH3-mimetics have not described any overt toxicities associated with single-agent use, but these agents are still early in clinical development. Therefore, we sought to identify approved drugs that could sensitize leukemic cells to ABT-263.<b>Experimental Design:</b> A screen identified dihydroartemisinin (DHA), a water-soluble metabolite of the antimalarial artemisinin. Using mouse and human leukemic cell lines, and primary patient-derived xenografts, the effect of DHA on survival was tested, and mechanistic studies were carried out to discover how DHA functions. We further tested <i>in vitro</i> and <i>in vivo</i> whether combining DHA with ABT-263 could enhance the response of leukemic cells to combination therapy.<b>Results:</b> DHA causes the downmodulation of MCL-1 expression by triggering a cellular stress response that represses translation. The repression of MCL-1 renders leukemic cells highly sensitive to synergistic cell death induced by ABT-263 in a mouse model of BCR-ABL⁺ B-ALL both <i>in vitro</i> and <i>in vivo</i> Furthermore, DHA synergizes with ABT-263 in human Ph⁺ ALL cell lines, and primary patient-derived xenografts of Ph⁺ ALL in culture.<b>Conclusions:</b> Our findings suggest that combining DHA with ABT-263 can improve therapeutic response in BCR-ABL⁺ B-ALL. <i>Clin Cancer Res; 23(24); 7558-68. ©2017 AACR</i>.