We live in an era of precision medicine, where the identification of novel biomarkers can reveal disease type or response, facilitating better treatment strategies and outcomes for patients. Despite the development of targeted treatments for breast cancer linked to specific biomarkers (eg. Her2 overexpression/Herceptin), many breast cancers are either unaffected or develop resistance. Clearly new treatment strategies and options are urgently needed. Our hypothesis: Significantly reducing the activity of an essential protein (with low levels in cancer cells) below a crucial survival threshold (using targeted inhibitors) preferentially induces death in cancer cells (but not normal cells with high levels)1. We identified Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator.
Here we describe in silico modelling, development and application of novel lysine (K) acetyltransferase inhibitors (KATi) targeting the essential MYST family member Tip60, a key protein involved in the DNA damage response and repair pathways. Significantly, we found Tip60 is down-regulated in breast cancer (unpublished data). We demonstrate that our proof-of-concept KATi, TH1834, significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation) in breast cancer, but not control, cell lines. Furthermore, TH1834 did not affect the activity of related MYST MOF, established by H4K16Ac, demonstrating specificity2. Using our KATi and organoid cultures we are exploring Tip60 dependent molecular mechanisms potentially underpinning breast cancer initiation and development.
Utilising a breast cancer tissue microarray (n=396) and staining for Tip60 we observed a significant dysregulation of both Tip60 expression and localisation in breast cancer biopsies. Preliminary analysis of the quantification of Tip60 staining (% cells stained, intensity, localisation) combined with clinicopathological data indicates that Tip60 is a breast cancer biomarker, indicative of a worse prognosis (unpublished data). Identifying subtypes with lower Tip60 levels provides a subtype-specific breast cancer therapeutic target for KATi.
Our work identifying specific patient cohorts (using a biomarker, Tip60 scoring) that can be targeted with a tailored treatment (KATi) is a precision medicine-based approach needed to improve breast cancer treatment.