Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a five-year survival rate of less than 10%, largely due to the lack of effective therapeutic options. Although pan-histone deacetylase (HDAC) inhibitors have demonstrated preclinical efficacy, their clinical application has been limited by dose-limiting toxicities. Selective HDAC inhibitors offer a potential solution by reducing toxicity while preserving antitumor activity. However, effective use of these agents requires identification of the specific HDAC isoforms responsible for therapeutic benefit in PDAC.
Methods and Results:
We investigated the combinatorial potential of selective HDAC inhibition in PDAC cell lines. Mocetinostat, an HDAC1/2/3 inhibitor, exhibited strong synergy with LMK-235, an HDAC4/5/6 inhibitor. While neither agent alone synergized with gemcitabine, their combination in triplet with gemcitabine produced robust synergistic cytotoxicity. Mechanistic studies using siRNA-mediated knockdown identified HDAC1, HDAC2, and HDAC6 as key mediators of this synergy.
To further validate these findings, we employed pharmacologic inhibitors: Romidepsin (HDAC1/2 inhibitor) and ACY-1215 (HDAC6 inhibitor). This combination, when administered with gemcitabine, showed potent synergy in multiple PDAC cell lines and significantly enhanced gemcitabine’s antitumor efficacy in PDAC xenograft models in vivo.
Conclusions:
Our findings demonstrate that concurrent inhibition of HDAC1, HDAC2, and HDAC6 is required to achieve maximal therapeutic synergy with gemcitabine in PDAC. These results provide a strong rationale for developing combination strategies targeting HDACs 1, 2, and 6 to improve outcomes for patients with PDAC.