Oral Presentation 28th Lorne Cancer Conference 2016

TRAIL causes deletions at the HPRT and TK1 loci. (#24)

Mark A Miles 1 , Nathan Hall 1 2 3 , Christine J Hawkins 1
  1. Department of Biochemistry and Genetics, LaTrobe Institute of Molecular Science, Bundoora, Victoria, Australia
  2. AgrioBio, LaTrobe University of Molecular Science, Bundoora, Victoria, Australia
  3. Life Sciences Computation Centre, VLSCI, Melbourne , Victoria, Australia
Genotoxic chemotherapy drugs, such as cisplatin and etoposide, have contributed to the increase in survival of patients treated for cancer, however there is an unfortunate potential for the subsequent development of therapy-induced “second cancers” due to the DNA damage provoked by these drugs in non-cancerous cells. A death receptor agonist, tumour necrosis factor-related apoptosis inducing ligand (TRAIL), has shown potential as an anti-cancer agent by activating the extrinsic apoptosis pathway and is currently in clinical trials. Surprisingly, we previously reported that cells of astrocyte (LN18) and fibroblast (MEF) origin acquire a high frequency of mutations at the HPRT reporter locus following TRAIL exposure[1]. TRAIL-mediated DNA damage was caspase and caspase-activated DNase (CAD) dependent. Conversely, drugs that target Bcl-2 and IAP proteins were non-mutagenic [2]. In this current study, we have shown that TRAIL increases mutation frequencies at the HPRT and also at the TK loci in the commonly used lymphoid TK6 cell line. The majority of TRAIL-induced mutants at both loci harbored deletions compared to mostly substitutions following exposure to the known mutagen ethylmethanesulfonate (EMS). The mutations induced by TRAIL are consistent with CAD mechanism of action, emphasizing the potentially mutagenic role of this apoptotic nuclease. Therefore, this study has provided insight into the types of genomic changes that can be provoked by TRAIL and the potential risks of second cancers in patients treated with TRAIL.
  1. Lovric, M.M. and C.J. Hawkins, TRAIL treatment provokes mutations in surviving cells. Oncogene, 2010. 29(36): p. 5048-60.
  2. Shekhar, T.M., Green, M.M., Rayner, D.M., Miles, M.M., Cutts, S.C. and Hawkins, C.J., Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells. Mutat Res, 2015. 777: p. 23-32.