Researchers from the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, CAS found that STAT3, an important oncogenic transcription factor but “undruggable”, is a new mechanistic target of rapamycin. This finding sheds lights on the pharmacological and pharmaceutical development of STAT3 inhibitors for cancer therapy.

Rapamycin is widely recognized as an inhibitor of mTOR, and has been approved for clinical use as an immunosuppressant. Recently, its potencies in anti-cancer, anti-aging, and neurodegenerative diseases have been emergingly established. Therefore, the exploration of other targets of rapamycin will further elucidate its underlying mechanisms of action and related drug development. 

In this study, the researchers used a quantitative chemical proteomics approach to profile the rapamycin targetome, and revealed 213 high-confidence candidate targets. Of these candidates, the researchers verified that the oncogenic transcription factor STAT3 is a bona fide protein binding partner of rapamycin, and its cellular activity can be regulated by rapamycin. With the help of multi-dimensional proteomics, they further demonstrated that rapamycin affects another oncogene, c-Myc, at least partially through STAT3. A JHH-7 xenograft mouse model showed that rapamycin reduces tumor growth and inhibited c-Myc and STAT3 expression. 

Altogether, the research is in support of STAT3 as a second mechanistic target of rapamycin. The data provided by this study suggest that rapamycin plays its anti-cancer roles in a synergistic “one stone three birds” manner by regulating mTOR, STAT3 and c-Myc together. This study provides new leads for the development of novel STAT3 and c-Myc inhibitors, which are both conventionally deemed 'undruggable'. 

Dr. ZHANG Yaoyang supervised this work. Ms. SUN Le, the first author on this paper, is a Ph.D. student in Dr. Zhang’s lab. The funding was provided by the Chinese Academy of Sciences, the National Program on Key Basic Research Project of China, the National Natural Science Foundation of China, the Natural Science Foundation of Shanghai, and the Shanghai Municipal Science and Technology Major Project.