Acquired resistance to venetoclax (ABT-199) int(14;18)positive lymphoma cells

// Juraj Bodo 1 , Xiaoxian Zhao 1 , Lisa Durkin 1 , Andrew J. Souers 2 , Darren C. Phillips 2 , Mitchell R. Smith 3 , Eric D. Hsi 1 1 Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA 2 Oncology Discovery, AbbVie, Inc., Chicago, IL, USA 3 Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Correspondence to: Eric D. Hsi, email: hsie@ccf.org Keywords: venetoclax, resistance, follicular lymphoma Received: April 15, 2016 Accepted: August 10, 2016 Published: September 20, 2016 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.