1. Academic Validation
  2. The small-molecule drug homoharringtonine targets HSF1 to suppress pancreatic cancer progression

The small-molecule drug homoharringtonine targets HSF1 to suppress pancreatic cancer progression

  • Am J Cancer Res. 2024 May 15;14(5):2072-2087. doi: 10.62347/XFJH3424.
Gui-Hong Li 1 2 Ying Miao 3 Huang Chen 3 Meng-Fei Xue 2 Jia-Yu Wang 3 Jing-Wen Zhang 3 Zheng-Fang Yi 3 Zhen-Liang Sun 2
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Southern Medical University Guangzhou 510515, Guangdong, P. R. China.
  • 2 Affiliated Fengxian Hospital, Southern Medical University Shanghai 201499, P. R. China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University Shanghai 200241, P. R. China.
Abstract

Heat shock factor 1 (HSF1), an essential transcription factor for stress response, is exploited by various tumors to facilitate their initiation, progression, invasion, and migration. Amplification of HSF1 is widely regarded as an indicator in predicting Cancer severity, the likelihood of treatment failure and reduced patient survival. Notably, HSF1 is markedly amplified in 40% of pancreatic Cancer (PC), which typically have limited treatment options. HSF1 has been proven to be a promising therapeutic target for multiple cancers. However, a direct small molecule HSF1 Inhibitor with sufficient bioactivity and reliable safety has not been developed clinically. In this study, we successfully established a high-throughput screening system utilizing luciferase reporter assay specifically designed for HSF1, which leads to the discovery of a potent small molecule inhibitor targeting HSF1. Homoharringtonine (HHT) selectively inhibited PC cell viability with high HSF1 expression and induced a markedly stronger tumor regression effect in the subcutaneous xenograft model than the comparator drug KRIBB11, known for its direct action on HSF1. Moreover, HHT shows promise in countering the resistance encountered with HSP90 inhibitors, which have been observed to increase heat shock response intensity in clinical trials. Mechanistically, HHT directly bound to HSF1, suppressing its expression and thereby inhibiting transcription of HSF1 target genes. In conclusion, our work presents a preclinical discovery and validation for HHT as a HSF1 Inhibitor for PC treatment.

Keywords

HHT; HSF1; HSP90 inhibitor resistance; pancreatic cancer; small molecule inhibitor.

Figures
Products