High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells.
Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax.
Biology Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada;
Sina
S
Oppermann
Biology Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada;
Jarkko
J
Ylanko
Biology Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada;
Yonghong
Y
Shi
Biology Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada;
Santosh
S
Hariharan
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
Christopher C
CC
Oakes
Department of Immunology, University of Toronto, Toronto, ON, Canada;
Patrick M
PM
Brauer
Biology Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada;
Juan C
JC
Zúñiga-Pflücker
Department of Medicine, McMaster University, Hamilton, ON, Canada;
Brian
B
Leber
Biology Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada; Sunnybrook Odette Cancer Center, Toronto, ON, Canada; and Department of Medical Biophysics and.
David E
DE
Spaner
Biology Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Sunnybrook Odette Cancer Center, Toronto, ON, Canada; and Department of Medical Biophysics and Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
David W
0000-0002-9266-7157
DW
Andrews
D000225:Adenine / Q000031:analogs & derivatives; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D060833:Cellular Microenvironment / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D021621:Imaging, Three-Dimensional; D007211:Indoles / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D052999:Quinazolinones; D013449:Sulfonamides; D051020:bcl-X Protein; C551803:ibrutinib; D000225:Adenine; C579720:venetoclax; D000077210:Sunitinib; C552946:idelalisib