Histone deacetylases (HDACs) inhibitors represent the first success of epigenetic-based cancer therapy. Several HDACs inhibitors have been approved for the clinical treatment of subtypes of hematological malignancies. Efforts in expanding the clinical benefits of HDACs inhibitors in solid tumors have never stopped through dozens of clinical trials.

Regardless of the tremendous efforts, the efficacy of HDACs inhibitors in solid tumors remains uncertain. Clinical trials at the moment tend to combine HDACs inhibitors with chemotherapy or other targeted therapies to enhance the clinical efficacy, yet they have met with limited success in solid tumors due to lack of mechanism-based combination design.

Scientists from Shanghai Institute of Materia Medica (SIMM) of Chinese Academy of Sciences made progress in demonstrating the therapeutic opportunities of HDACs inhibitors in combination with clinically available drugs in triple-negative breast cancer. The study was published in Cancer Cell on Sept 12, 2016.

Researchers took breast cancer, in particular triple-negative breast cancer, as a representative to understand mechanisms behind, and to further provide rationales for combo-therapy. They discovered a leukemia inhibitory factor receptor (LIFR) centered feedback loop that restrained the efficacy of HDACs inhibitors in breast cancer.

The mechanism involves the increased histone acetylation by HDACs inhibition at the LIFR gene promoter, which recruits BET family BRD4 and transcriptionally up-regulates LIFR. Up-regulated LIFR in turn activates Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and limits the response to HDACs inhibition.

These results provide important mechanistic insights to help explaining clinically observed ineffectiveness of HDACs inhibitors in solid tumors. They also provide the first evidence showing that the clinically available JAK inhibitor synergizes with HDACs inhibitors in treating triple-negative breast cancer, and hence identifies HDAC inhibitors-based therapeutic strategies that are ready to be tested in clinic.

Besides, the mechanisms discovered in this study seems not limited to breast cancer, as the authors also observed feedback activation of STAT3 in a broad spectrum of solid tumor cells. To explore therapeutic opportunities of JAK inhibitors and HDACs inhibitors in other solid tumors could be promising.

The work was supported by the National Natural Science Foundation of China, the Ministry of Science and Technology of China and Chinese Academy of Sciences.

Figure: Feedback activation of LIFR-STAT3 pathway confers ineffectiveness to HDAC inhibitors in breast cancer (Image by SIMM)