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Proteasome inhibition overcomes resistance to targeted therapies in B-cell malignancy models and in an index patient
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Journal Article
Proteasome inhibition overcomes resistance to targeted therapies in B-cell malignancy models and in an index patient
2025
Overview
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 effective across models and in primary chronic lymphocytic leukemia (CLL) cells, independently of their PI3Ki- or Bcl-2i-sensitivities. PI treatment consistently upregulated Bim and Mcl-1, while Bcl-2 increased in KARPAS1718 and CLL cells. Bcl-2i plus PI combinations led to an additive effect in these models. A multi-refractory CLL patient in the IMPRESS-Norway trial (NCT04817956) treated with Bcl-2i plus PI showed initial clinical improvement but relapsed within four months. Treatment induced Bim and Mcl-1 upregulation and reduced cytotoxic CD8
+
T-cell and CD56
dim
NK-cell populations. Our findings suggest that PIs may overcome resistance to targeted therapies, and warrant further studies to optimize clinical responses.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
1-Phosphatidylinositol 3-kinase
/ 45/77
/ 82/47
/ 96/106
/ 96/95
/ B-Lymphocytes - drug effects
/ Bcl-2-Like Protein 11 - metabolism
/ Biomedical and Life Sciences
/ Cells
/ Chronic lymphocytic leukemia
/ Drug Resistance, Neoplasm - drug effects
/ Humans
/ Kinases
/ Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
/ Leukemia, Lymphocytic, Chronic, B-Cell - pathology
/ Patients
/ Proteasome Inhibitors - pharmacology
/ Proteasome Inhibitors - therapeutic use
/ Proteins
/ Proto-Oncogene Proteins c-bcl-2 - metabolism
/ Quinazolinones - pharmacology
/ Quinazolinones - therapeutic use
/ Software
/ Toxicity
