The BH3-only protein NOXA is essential for apoptosis induction by BH3-mimetics targeting BCL2 or BCL-XL in DLBCL.

BCL2 inhibitors (BCL2i) have transformed the management of chronic lymphocytic leukaemia (CLL), but their use in more aggressive B-cell malignancies such as diffuse large B-Cell lymphoma (DLBCL) is complicated by the more heterogeneous nature of the disease. Successful responses are limited to a subset of patients, highlighting the need for robust biomarkers predicting sensitivity. Here, we investigated the underlying mechanisms of inherent resistance to the BCL2i ABT-199 and BCL-XL inhibitor A1331852, focusing on the roles of the principal pro-apoptotic BH3-only proteins NOXA and BIM. We show that NOXA deletion, but not BIM deletion, in BCL2 and BCL-XL-dependent DLBCL cells both in vitro and in vivo resulted in a highly significant enhanced resistance to both BCL2i and BCL-XL inhibitors. In contrast, NOXA deletion did not result in alteration of sensitivity to MCL1 inhibitors. NOXA loss was associated with increased stability and binding capacity of MCL1; binding of BIM to MCL1 was associated with resistance to ABT-199. Resistance to BCL2i and BCL-XL inhibitors was abrogated by suppression of MCL1 expression. In conclusion, we show that NOXA is essential for the effectiveness of BH3-mimetics targeting BCL2/BCL-XL; in the absence of NOXA, BIM displaced from BCL2/BCL-XL can be bound by MCL1.