BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199.
The Bcl-2 antagonist ABT-199 (venetoclax) has demonstrated promising clinical activity in patients with chronic lymphocytic leukemia (CLL). ABT-199 is strongly cytotoxic against unstimulated peripheral blood CLL cells in vitro but is much less effective against CLL cells that have received survival signals from the microenvironment. In particular, stimulation of CLL cells with CD40L results in substantial resistance mediated by induction of the antiapoptotic Bcl-2 family proteins Bcl-xL and Bfl-1. In this study, we investigated whether resistance to ABT-199 can be conferred by B-cell receptor (BCR) stimulation, which is another important survival signal from the leukemic microenvironment. We show that sustained BCR stimulation results in significant ABT-199 resistance, which correlates with induction of the antiapoptotic protein Mcl-1 and less consistently with downregulation of proapoptotic Bmf, Hrk, and BimEL A major role for Mcl-1 in conferring ABT-199 resistance is additionally supported by knockdown and enforced expression experiments with primary CLL cells. We further show that SYK, BTK, and phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitors significantly downregulate Mcl-1, but with different efficacy. Complete Mcl-1 downregulation was consistently achieved only with SYK inhibitors R406 and GS-9973 (entospletinib), whereas the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib in more than half of the cases had only a partial effect. The greater ability of SYK inhibitors to downregulate Mcl-1 correlated with their greater capacity to block BCR-mediated inactivation of GSK-3, a major negative regulator of Mcl-1. The finding that BCR signaling inhibitors differ in their ability to target Mcl-1 is relevant for the design of clinical trials combining these agents with ABT-199.
Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Trieste, Italy; Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland;
Kamil
K
Bojarczuk
Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Trieste, Italy;
Binu K
BK
Sasi
Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Trieste, Italy;
Stefania
S
Gobessi
Department of Hematology, Catholic University Hospital "A. Gemelli," Rome, Italy; and.
Idanna
I
Innocenti
Department of Medical and Surgical Sciences, University of Trieste, Trieste, Italy.
Gabriele
G
Pozzato
Department of Hematology, Catholic University Hospital "A. Gemelli," Rome, Italy; and.
Luca
L
Laurenti
Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Trieste, Italy;
Dimitar G
DG
Efremov
D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D010078:Oxazines / Q000494:pharmacology; D010880:Piperidines; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; D013449:Sulfonamides; C551803:ibrutinib; D000225:Adenine; C579720:venetoclax; C552946:idelalisib