title: Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells.
abstract: The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL.The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/ BIM complex and a decrease in mitochondrial potential. Interestingly the population of cells that survived venetoclax treatment showed increased p-ERK1/2 and p-BIM (S69), as well as a decrease in total BIM levels. Venetoclax resistant cells initially showed elevated levels of p-AKT and p-Foxo1/3a, a dissociation of BIM/BCL-2/BECLIN1 complex, and a decrease in SQSTM1/p62 level (indicating increased autophagy) together with a slight decline in BIM expression. After stable resistant cell lines were established, a significant reduction of BCL-2 levels and almost total absence of BIM was observed.The acquisition of these resistance phenotypes could be prevented via selective ERK/AKT inhibition or anti-CD20 antibody treatment, thus highlighting possible combination therapies for FL patients.
authors.affiliation: Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Juraj
authors.initials: J
authors.lastname: Bodo
authors.affiliation: Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Durkin
authors.affiliation: Oncology Discovery, AbbVie, Inc., Chicago, IL, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.affiliation: Oncology Discovery, AbbVie, Inc., Chicago, IL, USA.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Phillips
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000032:analysis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013449:Sulfonamides / Q000627:therapeutic use*; D014178:Translocation, Genetic
chemical_list: D000072224:Bcl-2-Like Protein 11; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C579720:venetoclax
keywords: follicular lymphoma; resistance; venetoclax