The Impact of the BCR Phenotype of Large B-cell Lymphoma on Ibrutinib Sensitivity

Large B-cell lymphoma (LBCL) is traditionally classified by cell-of-origin (COO) into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. A consensus clustering (CC) classification has proposed three metabolic/signaling subgroups: oxidative phosphorylation (Oxphos), B-cell receptor (BCR), and host-response (HR). We aimed to determine whether this novel CC classification predicts sensitivity to targeted kinase inhibitors, specifically the BTK inhibitor ibrutinib.

We assessed the in vitro cytotoxicity of ibrutinib, idelalisib (PI3K inhibitor), and everolimus (mTOR inhibitor) across characterized LBCL cell lines. Western blotting was used to evaluate potential protein markers (BCL-2, Thioredoxin, NRF2, and Thioredoxin reductase). Additionally, a systematic literature search of the PubMed database was conducted to extract ibrutinib IC₅₀ values for 55 unique LBCL cell lines categorized by CC class.

Our in vitro results demonstrated that Oxphos cell lines (Pfeiffer, Karpas-422) were significantly more resistant to ibrutinib compared to BCR cell lines (cell death 34% vs. 60%, p<0.001). No significant differences in sensitivity were observed for idelalisib or everolimus. Western blot analysis showed no statistically significant difference in the tested protein markers between classes. While literature data clearly identify sensitive LBCL cell lines, the IC₅₀ data revealed no significant difference in ibrutinib sensitivity when comparing groups by CC class alone (p=0.703). This is likely due to the limited amount of classified data and the limited number of available cell lines.

This premilinary in vitro data suggest a trend toward ibrutinib resistance in Oxphos-type cell lines. More research is warranted both in preclinical models as well as in clinical datasets.