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

## TL;DR

The BH3-only protein NOXA is crucial for the effectiveness of BCL2/BCL-XL inhibitors in treating diffuse large B-cell lymphoma.

## Contribution

This study identifies NOXA as a key determinant of sensitivity to BH3-mimetic drugs in DLBCL, distinct from BIM.

## Key findings

- NOXA deletion significantly increases resistance to BCL2 and BCL-XL inhibitors in DLBCL cells.
- BIM displacement from BCL2/BCL-XL can be bound by MCL1 in the absence of NOXA, causing resistance.
- MCL1 inhibition can overcome resistance caused by NOXA loss.

## Abstract

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.