Proteasome inhibitor carfilzomib complements ibrutinib’s action in chronic lymphocytic leukemia

Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia

“…In contrast, similar to present investigation, kinase inhibitors that impact components of BCR pathway did not induce apoptosis. Recent investigations using similar model system suggested carfilzomib, an endoplasmic reticulum (ER) stress agent, as a potential partner with ibrutinib (36). The positive interaction between these drugs was prevalent at different times after start of ibrutinib.…”

Precision medicine for cancer with next-generation functional diagnostics

“…Although ex vivo testing of patient samples has now become routine in investigations of basic biological mechanisms in haematological malignancies and in drug discovery (for example, recently, in 30 patients with chronic lymphocytic leukaemia (CLL), for whom the combination of carfilzomib and ibrutinib was discovered to be effective 69 ), its diagnostic potential has yet to be fully realized. These recent studies demonstrate that such direct patient testing might lead to patient benefit without knowledge of the underlying biology or mutations, which complements clinical scenarios in which treatments have been found to yield benefit when matched to specific mutations.…”

Carfilzomib Triggers Cell Death in Chronic Lymphocytic Leukemia by Inducing Proapoptotic and Endoplasmic Reticulum Stress Responses

“…Therefore, combination therapy that targets distinct biological pathways in CLL pathogenesis represents a significant step outside of the conventional chemotherapy-based approach. Accordingly, we recently identified carfilzomib, a Food and Drug Administration (FDA)-approved second-generation ubiquitin-proteasome pathway (UPP) inhibitor (4), as a potent pharmacologic agent that causes cytotoxicity in CLL cells before or after treatment with ibrutinib (5-9), an irreversible inhibitor of Bruton’s tyrosine kinase (10). …”