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Volume 3, Issue 4
J Clin Epigenet
ISSN: 2472-1158
Epigenetics 2017
November 06-08, 2017
EPIGENETICS & CHROMATIN
November 06-08, 2017 | Frankfurt, Germany
2
nd
International Congress on
J Clin Epigenet 2017, 3:4
DOI: 10.21767/2472-1158-C1-003
Targeting histones and HDACs to bypass resistance mechanisms in gastric cancers: Relevance for
immunogenic cell death and immunotherapy
Christian Gaiddon
Inserm U1113, France
G
astric cancer remains a health issue in European countries with an average survival of 10 months due to a late diagnosis
and the low efficiency of the standard therapies (e.g. cisplatin) on advanced cancers. One of the causes of cisplatin
inefficiency is the high rate of mutation in the tumor suppressor gene p53. This emphasizes the necessity to develop innovative
therapeutic strategies. To this end, we investigate the response to cisplatin using whole genome, mi-Rome, and proteome
analyses to identify key altered signaling pathways. We identified several epigenetic regulators, including HDACs. Based
on these findings, in collaboration with chemists, we developed several strategies to target histones and HDACs to treat
gastric cancers. We identified a ruthenium complex that interacts directly with histones and causes alterations in metabolic
pathways (e.g. unfolded protein response pathway) to induce immunogenic cell death. This mode of action allows this drug
to bypass resistance mechanisms of cisplatin, such as p53 mutations. In parallel, we analyzed the effects of combinatory
treatment associating cisplatin with pan or selective HDAC inhibitors. We found that they cooperate to induce synergistic
cytotoxicity on gastric cancer cells. Interestingly, the combination of HDAC inhibitors and cisplatin inhibits p53 expression
by a transcriptional mechanism. Surprisingly, despite the down-regulation of p53 protein levels, the synergistic induction of
apoptosis by the combinatory treatment is dependent upon p53. However, we show that the combination of drugs in cells with
p53 mutation is still able to induce a synergistic cytotoxic effect independently of apoptosis but rather through autophagy cell
death. Together our work proposed novel and innovative anticancer strategies for gastric cancer allowing to bypass resistance
mechanism by targeting epigenetic regulators or histones. By inducing immunogenic cell death, these therapies may cooperate
with the most recent immunotherapeutic approaches develop to treat cancers and alleviate some of their limitations.