title: Cell-Intrinsic Determinants of Ibrutinib-Induced Apoptosis in Chronic Lymphocytic Leukemia.
abstract: Purpose:Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) and CLL with del17p. Mechanistically, ibrutinib interferes with B-cell receptor (BCR) signaling as well as multiple CLL cell-to-microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted.Experimental Design:We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole-exome sequencing and SNP 6.0 array profiling. We exposed these samples to 0.25 to 5 μmol/L of ibrutinibex vivoand measured apoptosis fractions as well as BCR signaling by immunoblotting. We disruptedTP53in HG3, PGA1, and PG-EBV cell lines and measured BCR signaling and ibrutinib responses.Results:CLL samples demonstrated a surprisingly wide range ofex vivosensitivities to ibrutinib, with IC50values ranging from 0.4 to 9.7 μmol/L. Unmutated IGVH status, elevated ZAP70 expression, and trisomy 12 were associated with heightened sensitivity to ibrutinib treatment. Five CLL samples were substantially more resistant to ibrutinib following relapse from chemotherapy; of these, three had acquired a del17p/TP53-mutated status. A validation sample of 15 CLL carryingTP53mutations, of which 13 carried both del17p and aTP53mutation, confirmed substantially less sensitivity to ibrutinib-induced apoptosis.Conclusions:This study identifies that CLL harboring del17p/TP53-mutated cells are substantially less sensitive to ibrutinib-induced apoptosis than del17p/TP53wild-type cells.Clin Cancer Res; 23(4); 1049-59. ©2016 AACR.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Nisar A
authors.initials: NA
authors.lastname: Amin
authors.affiliation: Janssen R&D, LLC, New Jersey.
authors.forename: Sriram
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kamlai
authors.initials: K
authors.lastname: Saiya-Cork
authors.affiliation: Department of Statistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan. smalek@med.umich.edu.
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D017209:Apoptosis / Q000187:drug effects; D054316:Biomarkers, Pharmacological; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D010880:Piperidines; D020641:Polymorphism, Single Nucleotide; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000073359:Exome Sequencing
chemical_list: D054316:Biomarkers, Pharmacological; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C551803:ibrutinib; D000225:Adenine