Poster Presentation 28th Lorne Cancer Conference 2016

Uniform pattern of histone modifications define early stress induced drug tolerance in cancer (#139)

Abdullah Emran 1 2 , Dinoop Ravindran Menon 1 , Richard A Sturm 1 , Brian Gabrielli 2 , Meenhard Herlyn 3 , Helmut Schaider 1 2
  1. Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia
  2. The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia
  3. The Wistar Institute, Philadelphia, PA 19104, USA

Resistance to chemotherapy and targeted therapies is a major problem for cancer treatment. Acquired drug resistance is not only dependent on somatic mutations or drug efflux suggestive of alternative mechanisms like epigenetic changes and chromatin remodeling. Recent studies also suggest drug holidays after initial treatment with a drug re-sensitizing cancer cells to the same drug. We recently have identified early stress induced multi-drug resistant cancer cells termed induced drug tolerant cells (IDTCs).

Transcriptional active histone marks like H3K4me3 and repressive marks like- H3K9Me3 and H3K27me3 were altered (upregulation of H3K9Me3 and downregulation of H3K4Me3 and H3K27Me3) in IDTCs compared to parental cancer cells. These data were consistent in all of five cancer types including melanoma, lung, colon, breast and hepatocellular carcinoma in response to chemo or targeted therapy, indicating that this effect is a common mechanism of initial drug resistance regardless of treatment or cancer types.  Similar histone modification patterns were observed under conditions of nutrient starvation, if a drug holiday was provided dynamic switching of histone modification was observed resembling histone modifications and sensitivity to the drug of the parental population. Microarray data suggest that there are multiple genes regulating similar histone modifications across different cancer types. Along with that, different pro-survival pathways like ERK, AKT, MTOR and AMPK were upregulated in all five cancer types.   

Global histone modifications render cancer cells to transform into IDTCs characterized by a distinct morphology, expression of IDTC markers like CD271, multidrug resistance and activation of pro-survival signaling. Histone modifications, chromatin remodelling, and DNA methylation act in cohort to maintain the euchromatin and heterochromatin state of IDTCs. We aim to further elucidate target genes of active and inactive histone modifiers in IDTCs crucial for the transition of early- to acquired permanent drug resistance.