Enhancing Paclitaxel Efficacy in Solid Tumor Models through Selective HDAC Inhibition by ACY-241

The abstract discusses the potential of combining HDAC inhibitors with chemotherapy drugs for treating cancer. It highlights the clinical benefits of such combinations, as seen in ovarian cancer and hormone receptor therapy-refractory breast cancer. However, the toxicity of pan-HDAC inhibitors limits their use in combination therapies. The development of selective HDAC inhibitors with better safety profiles is being pursued.

A new HDAC inhibitor, ACY-241, is being tested in combination with other drugs for treating multiple myeloma. It shows promise due to its reduced side effects compared to nonselective HDAC inhibitors and retains anticancer potential. The study explores the activity of ACY-241 combined with paclitaxel in solid tumors.

In various solid tumor cell lines, the combination of ACY-241 and paclitaxel resulted in increased inhibition of cell growth and cell death compared to single treatments. The combination was also more effective in xenograft models of pancreatic and ovarian cancer and was well tolerated in animals. Similar results were found when another HDAC6 inhibitor was combined with paclitaxel.

The study suggests that paclitaxel induces multipolar spindle formation, leading to abnormal cell division and death. The combination treatment with ACY-241 and paclitaxel resulted in more frequent multipolar spindles in mitotic cells, indicating a potential block in S phase entry and increased aberrant mitoses.

Molecularly, paclitaxel enhances microtubule stability and α-tubulin acetylation. HDAC6 regulates α-tubulin acetylation, and ACY-241 treatment increases α-tubulin hyperacetylation. The combination treatment led to further increased hyperacetylation, suggesting a synergistic effect on tubulin biology.

The study concludes that the increased efficacy of ACY-241 combined with paclitaxel, along with the anticipated superior safety profile of a selective HDAC6 inhibitor, supports the clinical development of this combination for advanced solid tumors. The findings were presented at a conference by the authors.