Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199)

• Published in: Leukemia Vol. 31; no. 9; pp. 1872 - 1881
• Main Authors: Patel, V M, Balakrishnan, K, Douglas, M, Tibbitts, T, Xu, E Y, Kutok, J L, Ayers, M, Sarkar, A, Guerrieri, R, Wierda, W G, O'Brien, S, Jain, N, Stern, H M, Gandhi, V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2017; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/2; 13/31; 38/39; 38/61; 38/62; 38/91; 631/67/1059; 631/80/82/23; 692/308/2779/109/1940; 692/4028/67/1059/99; 692/699/1541/1990/283/1895; 82; 82/80; 96; Agent Orange; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - drug effects; Arrays; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer Research; Care and treatment; Chronic lymphocytic leukemia; Clinical trials; Critical Care Medicine; Drug Synergism; Gene expression; Hematology; Humans; In vitro methods and tests; Inhibitors; Intensive; Internal Medicine; Isoquinolines - pharmacology; Isoquinolines - therapeutic use; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphatic leukemia; Lymphocyte receptors; Lymphocytes B; Lymphoma; Medicine; Medicine & Public Health; Non-Hodgkin's lymphoma; Oncology; original-article; Patients; Polymerase chain reaction; Protein arrays; Proteins; Purines - pharmacology; Purines - therapeutic use; Regulators; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Transcription; Tumor Cells, Cultured; Tumor microenvironment; Tumors
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.382

Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin’s lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo -cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.