Abstract 5170: HDAC inhibitors and the mechanism of resistance in colorectal cancer: RAS and MYC - the partners in crime

Abstract

Abstract Although histone deacetylase inhibitors (HDACi) are considered a promising novel therapeutic approach in the light of their potent tumour-selective effects, the use of these inhibitors for treatment of colorectal cancer (CRC) have thus far demonstrated limited success as a monotherapy. What this eventually boils down to is our incomplete understanding of the molecular mechanisms, the impact of oncogenes, and thus the key pathways through which HDACi affect tumour cell growth. To shed further light on this, the involvement of oncogenic RAS - a key driver of CRC, in determining the responsiveness to HDACi has been explored. By using cell line model systems harbouring conditional oncogenic NRAS, KRAS and HRAS, we uncovered an oncogenic RAS-dependent “safeguard” mechanism imposed in order to evade the cytotoxic effect of HDACi and therefore apoptosis. Characteristically, cells harbouring oncogenic RAS were observed to undergo a reversible senescence-like growth arrest in G2, allowing for re-entry into cell cycle following the withdrawal of HDACi. This mechanism is implemented as a consequence of the direct targeting of RAS by HDAC inhibition, which resulted in a further amplified GTP-binding activity and subsequent signalling through the MAPK pathway. The observed outcome was an increase in the priming of MYC for ubiquitin-mediated proteasomal degradation, thereby enabling the cells to exit the cell cycle and enter the protective state of G2 arrest. This process was functionally reversed with a conditional non-degradable MYC (T58A/S62A), which in turn rendered the cells more susceptible to undergo apoptosis. Conclusively, in the context of a constitutively activating RAS mutation, the prospect of HDACi treatment was effectively improved using current MAPK-targeted therapy by preventing the observed pro-oncogenic effect of the HDACi treatment alone. Note: This abstract was not presented at the meeting. Citation Format: Sylvia S. Ispasanie, Lena Boehme, Martin Eilers, Tilman Brummer, Kathleen Klotz-Noack, Natalia Kuhn, Bastian Gastl, Christine Sers. HDAC inhibitors and the mechanism of resistance in colorectal cancer: RAS and MYC - the partners in crime [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5170. doi:10.1158/1538-7445.AM2017-5170