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Feed‐forward activation of STAT3 signaling limits the efficacy of c‐Met inhibitors in esophageal squamous cell carcinoma (ESCC) treatment
Author(s) -
Zhao Di,
Chen Jie,
Wang Yan,
Zhang Lingyuan,
Zhang Jing,
Zhang Weimin,
Fan Jiawen,
Li Jinting,
Zhan Qimin
Publication year - 2021
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.23306
Subject(s) - autocrine signalling , biology , stat3 , cancer research , stat protein , leukemia inhibitory factor , hepatocyte growth factor , signal transduction , receptor , interleukin 6 , cytokine , immunology , microbiology and biotechnology , biochemistry
c‐Hepatocyte growth factor receptor (Met) inhibitors have demonstrated clinical benefits in some types of solid tumors. However, the efficacy of c‐Met inhibitors in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we discovered that c‐Met inhibitors induced “Signal Transducer and Activator of Transcription (STAT3)‐addiction” in ESCC cells, and the feedback activation of STAT3 in ESCC cells limits the tumor response to c‐Met inhibition. Mechanistically, c‐Met inhibition increased the autocrine of several cytokines, including CCL2, interleukin 8, or leukemia inhibitory factor, and facilitated the interactions between the receptors of these cytokines and Janus Kinase1/2 (JAK1/2) to resultantly activate JAKs/STAT3 signaling. Pharmacological inhibition of c‐Met together with cytokines/JAKs/STAT3 axis enhanced cancer cells regression in vitro. Importantly, combined c‐Met and STAT3 inhibitors synergistically suppressed tumor growth and promoted the apoptosis of tumor cells without producing systematic toxicity. These findings suggest that inhibition of the STAT3 feedback loop may augment the response to c‐Met inhibitors via the STAT3‐mediated oncogene addiction in ESCC cells.