Targeting histone H3K36me3-deficient cancers

12^th World Cancer Conference

September 26-28, 2016 London, UK

Timothy C Humphrey

University of Oxford, UK

Posters & Accepted Abstracts: J Cancer Sci Ther

Abstract :

Histone H3 lysine 36 trimethylation (H3K36me3) plays a central role in both orchestrating the DNA damage response and in suppressing tumorigenesis. Accordingly SETD2-dependent H3K36me3 is frequently lost in a number of cancer types, including high-grade pediatric gliomas (>50%) and metastatic renal carcinomas (~60%), for which prognosis is poor. These findings identify loss of this histone mark to be an important potential therapeutic target. We have identified an evolutionarily conserved synthetic lethal interaction between histone H3K36me3 deficiency and inhibition of the cell cycle regulator WEE1. We show that H3K36me3-deficient human cells are selectively killed with the WEE1 inhibitor, AZD1775. Cell death is associated with replication stress, DNA damage and apoptosis. An in vivo experiment in SETD2-deficient A498 xenografts showed that treatment with AZD1775 regress tumors, producing a marked reduction in tumor size compared with vehicle-treated control. We have also developed a companion biomarker to detect H3K36me3 loss in patient tissue microarrays (TMAs). As AZD1775 is already in Phase II clinical trials, we anticipate these findings will be of clinical relevance.

Biography :

Email: humphreytc@gmail.com