Poster Presentation Lorne Infection and Immunity 2020

BCL-XL inhibition by BH3 mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK cell lymphoma (#164)

Nenad Sejic 1 2 , Rosemary J. Tierney 3 , Catherine Chang 1 , Ping Lan 1 , Andrew I. Bell 3 , Guillaume Lessene 1 2 , Heather M. Long 4 , Andreas Strasser 1 2 , Claire Shannon-Lowe 4 , Gemma L. Kelly 1 2
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK
  4. Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, UK

Epstein-Barr virus (EBV) is an oncogenic gamma-herpesvirus that contributes to 2% of the global cancer burden, typically inducing malignancies of B or epithelial cell origin. Despite this oncogenic potential, EBV persists asymptomatically in the memory B cell compartment of approximately 90% of adults. Infection of T or NK cells with EBV, a rare event that is not part of the normal virus life cycle, can lead to the development of highly chemoresistant diseases such as Extranodal NK/T cell lymphoma (ENKTL). ENKTL has a near 100% association with EBV and patients are regularly immunocompetent thus implicating a role for EBV in disease pathogenesis. The rarity of ENKTL has limited our understanding of the viral contribution and also the mechanisms of drug resistance.

In our study, human ENKTL cell lines were assayed for expression of EBV genes and components of the intrinsic apoptotic pathway. Furthermore, we have investigated the chemosensitivity of the tumour cell lines to conventional chemotherapeutics and to BH3-mimetic drugs, that can trigger the intrinsic apoptotic pathway, either as single agents or in combination with one another. 

Reflecting primary tumours, ENKTL cell lines exhibit an EBV gene expression pattern known as latency II, defined by expression of the viral oncogenes LMP1 and LMP2. Diverse expression levels were observed across the cell line panel with regards to the BCL-2 family proteins where high viral LMP1 was correlated with elevated anti-apoptotic BCL-XL protein and inversely correlated with tumour suppressor pro-apoptotic proteins, BIM and BID. Conventional DNA damaging drugs were not potent inducers of apoptosis in ENKTL cell lines. However, apoptosis could be induced to varying degrees with the BH3-mimetic A-1331852, an inhibitor of BCL-XL. A-1331852 was most effective, particularly in LMP1-negative cell lines, when anti-apoptotic MCL-1 was additionally targeted by BH3-mimetics or genetically deleted. Additionally, A-1331852 treatment alone was well-tolerated and successfully delayed tumour latency in NSG mice xenotransplanted with the SNK6 cell line.

These data suggest that viral LMP1 status influences sensitivity to specific BH3-mimetics. Overall though, ENKTL cell lines showed a primary survival dependence on BCL-XL that could be exploited to provide a much needed novel therapeutic option for ENKTL.