Proteasome inhibition overcomes resistance to targeted therapies in B-cell malignancy models and in an index patient.

ABSTRACT: Treatment of B-cell malignancies with the PI3K inhibitor (PI3Ki) idelalisib often results in high toxicity and resistance, with limited treatment alternatives for relapsed/refractory patients since idelalisib is recommended as a later or last line therapy. To investigate resistance mechanisms and identify alternative treatments, we studied functional phenotypes of idelalisib-resistant B-cell malignancy models. The idelalisib-resistant KARPAS1718 model remained sensitive to Bcl-2 inhibitors (Bcl-2i), whereas the resistant VL51 model showed reduced sensitivity compared to parental cells. Sensitivity correlated with phosphorylation and expression of the Bcl-2 family members Bcl-2 and Bim. Target addiction scoring revealed high dependence on the proteasome, and proteasome inhibitors (PI) were

SUBMITTER: Hermansen JU 

PROVIDER: S-EPMC12287370 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature