SETD2-dependent histone H3 lysine 36 trimethylation (H3K36me3) plays a central role in both maintaining genome stability and in suppressing tumorigenesis, and is frequently depleted in particular cancer types. We find this histone mark plays an important role in promoting homologous recombination (HR) repair of DNA double-strand breaks. Further, H3K36me3 also performs an essential role in facilitating DNA replication following WEE1 kinase inhibition, through promoting efficient deoxyribonucleotide synthesis. Accordingly, H3K36me3-deficient cancers can be specifically targeted using the WEE1 inhibitor, AZD1775, resulting in replicative catastrophe and cell death. The use of AZD1775 to target H3K36me3-deficient cancers is now in clinical trials. Mechanistic insights into the targeting of H3K36me3-deficient cancers with AZD1775 and its implications will be presented.
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
Medical Research Council; Cancer Research UK; Clarendon Scholarship; Swiss National Science Foundation
The author has declared no conflicts of interest.
Despite successes in the treatment of melanoma patients with checkpoint inhibitors (CI), most patients do not respond to CI alone and a high unmet medical need remains for these patients. One promising approach is to enhance the immunogenicity and alter the tumor microenvironment from a more immune-deserted to an immune-inflamed phenotype by means of combination therapy. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes (e.g. histone deacetylases (HDAC) inhibitors) are particularly promising.
Tumor bearing animals (CT26 and C38 syngenic models) were treated with 4SC-202, an orally available clinical stage combined HDAC class I/LSD1 inhibitor, or CIs PD-(L)-1 alone as well as in combination. Tumor growth was assessed continuously and after approx. 2 weeks of treatment tumors were excised and analyzed by flow cytometry and gene expression profiling. Additionally, animals not intended for these analyses were further monitored and tumor growth/survival was monitored.
4SC-202 treatment led to an increase of MHC molecules and enhanced expression of inflammatory markers like IFN-γ and various chemokines in tumors. Furthermore, detailed analysis of the tumor revealed that 4SC-202 strongly altered the immune cell composition and particularly the number of cytotoxic T cells (CTL) was markedly increased. Importantly, subsequent combination treatment of 4SC-202 with CIs in syngenic animal models showed a strong synergistic effect resulting in significant longer survival in both models leading to 55% of tumor free animals (C38 model).
ClinicalTrials.gov Identifier:
NCT03278665
NCT03278665
NCT03278665
4SC AG
R. Bartz: I do not conduct activities that would involve a conflict of interest with CME-accreditable training, but that in the past 2 (two) years I have been a paid employee of 4SC AG.
Has not received any funding