Establishment of Bruton Tyrosine Kinase Inhibitor-Resistance Related Gene Signature to Predict Prognosis and Identification of TRIP13 As a Chemotherapeutic Target in Diffuse Large B-Cell Lymphoma

Background: Bruton tyrosine kinase inhibitor (BTKi) combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is a major cause of relapse and death in DLBCL. This study aims to explore the relationship between BTKi-resistance related genes (BRRGs) and DLBCL prognosis, and to clarify the function and mechanism of key resistance genes.

Results: In this study, we analyzed transcriptome data from parental and ibrutinib-resistant clone cell lines (GSE138126) and identified 1186 differentially expressed genes (DEGs), with 552 upregulated and 634 downregulated in the ibrutinib-resistant group. The GSE31312 dataset was used as the training cohort, while GSE87371 and GSE10846 served as external validation cohorts. Univariate Cox regression analysis identified 247 BRRGs associated with overall survival (OS). LASSO regression and tenfold cross-validation further identified 10 key BRRGs (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) to construct a prognostic signature. The resistance score formula based on 10-BRRGs is: Resistance Score=(0.2242×CARD16)+(0.0064×TRIP13)+(0.0174×PSRC1)+(0.0276×CASP1)+(0.0118×PLBD1)+(0.0627×CARD6)+(−0.0394×CAPG)+(−0.0661×CACNA1A)+(−0.3578×CDH15)+(0.6447×NDUFA4). Patients were divided into high- and low-resistance score groups based on the median resistance score. Kaplan-Meier survival analysis showed that patients with high-resistance scores had worse OS compared to those with low-resistance scores in both the training and validation cohorts. Additionally, the BRRGs signature exhibited good predictive efficacy for 1-year, 3-year, and 5-year OS, with AUC values of 0.731, 0.761, and 0.777, respectively. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Furthermore, we identified TRIP13 as a key resistance gene in this signature and found that TRIP13 was overexpressed in DLBCL and BTKi-resistant DLBCL cell lines. Knockdown of TRIP13 inhibited cell proliferation, promoted apoptosis, and enhanced the apoptotic effect of BTKi in vivo and in vitro. Mechanistically, these effects were mediated through the Wnt/β-catenin signaling pathway.

Conclusion: Our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL. Additionally, TRIP13 might be a potential therapeutic target for resistant DLBCL.

No relevant conflicts of interest to declare.