Abstract 4710: Deactylases in multiple myeloma: Expression, inhibition and resistance to inhibition

Abstract

Abstract Deacetylases (DACs) are a highly conserved group of enzymes that regulate a myriad of cellular functions through deacetylation of histones, transcription factors and molecular chaperones. Altered DAC expression is significantly associated with poor prognosis in solid and haematological malignancies, however the expression pattern and correlation of dysregulated expression to patient outcome has not been characterized in multiple myeloma (MM) cells. To address this, quantitative PCR was performed for DAC1-11 on MM (n=60) and normal plasma cells (n=11) purified from bone-marrow (BM) samples. Analyses revealed that median levels of all DACs, with the exception of DAC1 and DAC11, were significantly altered in MM. Interestingly, patients with increased DAC1, 2 and 6 levels had a significantly shorter progression-free survival from diagnosis compared to patients with lower levels. Inhibitors to DACs (DACi) are currently being used in clinical trials of multiple myeloma (MM), either alone or in combination with other novel and conventional anti-MM agents. Despite the rapid advancement in the use of DACi in MM therapy, it is still not clear which DAC needs to be inhibited to attain maximal MM cell death. To determine this, pan-inhibitors (LBH589 and SAHA) or isoform-specific inhibitors (FK228 and Tubacin) were tested for their cytotoxic potential on BM mononuclear cells from MM patients (n=10). Flow cytometric enumeration of CD38hi/CD45neg/APO2.7pos cell populations was performed to determine the proportion of apoptosis after 48 hours. Results indicated that inhibiting Class I DAC induced maximal MM cell death (75-90%) in 7/10 patient samples tested. Further experiments will include specifically targeting Class I DAC (DAC1, 2, 3 and 8) to determine which of these contribute to MM cell biology. Although DACi clinical trials show promising results, some patients are non-responsive to DACi therapy. Human myeloma cell lines (HMCLs) were used as a paradigm to identify genes associated with DACi resistance. Gene expression analysis was performed on nine HMCLs pre-determined to be DACi-sensitive or -resistant to identify genes differentially regulated between these categories. Of the 97 genes that were differentially regulated, 35-genes had >80% correlation (positive or negative) to DACi-sensitivity. Future work will include validation of these genes to identify candidate biomarkers that can be used to predict the response of an MM patient to DACi-response. In conclusion, this study has established that DAC levels are altered in MM and this dysregulation correlates to poor outcome, and inhibiting class I DAC is critical to induce maximal MM cell death. In addition, preliminary data indicates the existence of a gene signature associated with DACi-sensitivity in MM cells providing the framework to identify candidate biomarkers to predict response of an MM patient to DACi therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4710. doi:1538-7445.AM2012-4710