# Bcl-2 inhibitor resistance in diffuse large b-cell lymphoma: establishing a prognostic signature and targeting alpha protein kinase 1

## TL;DR

This study identifies a new method to predict outcomes in lymphoma patients and suggests a potential new drug target to improve treatment effectiveness.

## Contribution

A novel Bcl-2 signature and the identification of ALPK1 as a target to overcome venetoclax resistance in DLBCL.

## Key findings

- The Bcl-2 signature effectively predicts prognosis in diffuse large B-cell lymphoma patients.
- Inhibiting ALPK1 reduces cancer cell growth and enhances venetoclax's effectiveness.
- ALPK1 inhibition suppresses the ALPK1/NFκB signaling pathway when combined with venetoclax.

## Abstract

Drug resistance in diffuse large B-cell lymphoma (DLBCL) contributes to poor prognosis in 30–40% of newly diagnosed patients in the era of first-line rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. Targeting Bcl-2 has been shown to target for improve the prognosis of these patients, based on the clinical trials of its inhibitor, venetoclax. However, venetoclax resistance in DLBCL remains a challenge. Methods: The ‘WGCNA’ package was used to comprehensively screen for Bcl-2 inhibitor-resistant genes (Bcl-2RGs) and the Bcl-2RGs signature was established using LASSO regression analysis with ten-fold cross-validation. Results: The Bcl-2 signature is an effective prognostic prediction model using Gene Expression Omnibus data analysis. In addition, we demonstrated that the inhibition of alpha protein kinase 1 (ALPK1) decreased the proliferation of DLBCL cells and increased apoptosis. ALPK1 inhibitor treatment synergized with venetoclax to suppress the ALPK1/NFκB signaling pathway. Conclusion: Overall, we showed that the Bcl-2 signature could predict the prognosis of patients with DLBCL, and that ALPK1 could be a promising target for sensitizing patients with DLBCL to venetoclax therapy.

The ‘WGCNA’ package was used to comprehensively screen for Bcl-2 inhibitor-resistant genes (Bcl-2RGs) and the Bcl-2RGs signature was established using LASSO regression analysis with ten-fold cross-validation. Results: The Bcl-2 signature is an effective prognostic prediction model using Gene Expression Omnibus data analysis. In addition, we demonstrated that the inhibition of alpha protein kinase 1 (ALPK1) decreased the proliferation of DLBCL cells and increased apoptosis. ALPK1 inhibitor treatment synergized with venetoclax to suppress the ALPK1/NFκB signaling pathway. Conclusion: Overall, we showed that the Bcl-2 signature could predict the prognosis of patients with DLBCL, and that ALPK1 could be a promising target for sensitizing patients with DLBCL to venetoclax therapy.

The Bcl-2 signature is an effective prognostic prediction model using Gene Expression Omnibus data analysis. In addition, we demonstrated that the inhibition of alpha protein kinase 1 (ALPK1) decreased the proliferation of DLBCL cells and increased apoptosis. ALPK1 inhibitor treatment synergized with venetoclax to suppress the ALPK1/NFκB signaling pathway. Conclusion: Overall, we showed that the Bcl-2 signature could predict the prognosis of patients with DLBCL, and that ALPK1 could be a promising target for sensitizing patients with DLBCL to venetoclax therapy.

Overall, we showed that the Bcl-2 signature could predict the prognosis of patients with DLBCL, and that ALPK1 could be a promising target for sensitizing patients with DLBCL to venetoclax therapy.