Blocking STAT3 signaling augments MEK/ERK inhibitor efficacy in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the world’s leading causes of death, and its primary clinical therapy relies on surgical resection, chemotherapy, radiotherapy, and chemoradiotherapy. Although the genomic features and clinical significance of ESCC have been identified, the outcomes of targeted therapies are still unsatisfactory. Here, we demonstrate that mitogen-activated protein kinase (MAPK) signaling is highly activated and associated with poor prognosis in patients with ESCC. Mitogen-activated protein kinase kinase (MEK) inhibitors efficiently blocked the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in ESCC, while signal transducer and activator of transcription 3 (STAT3) signaling was rapidly activated. Combined STAT3 inhibition prevented the emergence of resistance and enhanced MEK inhibitor-induced cell cycle arrest and senescence in vitro and in vivo. Mechanistic studies revealed that the suppressor of cytokine signaling 3 (SOCS3) was downregulated, resulting in an increase in STAT3 phosphorylation in MEK-inhibited cells. Furthermore, chromatin immunoprecipitation showed that ELK1, which was activated by MEK/ERK signaling, induced SOCS3 transcription. These data suggest that the development of combined MEK and STAT3 inhibition could be a useful strategy in ESCC targeted therapy.

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

“…Accumulating evidence shows that RTKs and their related pathways are frequently dysregulated in OSCC [13,[46][47][48]. IGF1R, as a transmembrane glycoprotein and stress-receptor, could feel the stress outside and send these stress signals to intracellular, activating downstream pathways to regulate cell proliferation, migration, and chemotherapeutic resistance [14].…”

“…In several recent studies, dysregulated RTK family members were found in OSCC patients [ 12 , 13 ]. As ‘stress-receptors’, they can receive and transmit extracellular ‘harsh’ messages such as warnings about low oxygen levels to the cytoplasm, and initiate the intracellular downstream signal cascade to promote the growth, invasion, metabolism, and resistance phenotype of tumour cells [ 14 ].…”

Single-Cell Transcriptomics of Endothelial Cells in Upper and Lower Human Esophageal Squamous Cell Carcinoma

“…The abovementioned angiogenic processes are the major anti-angiogenic targets, and some critical genes were confirmed to be effective previously and consistent with our findings. STAT3 is a key transcription factor involved in wide cellular processes, and a previous study found blocking the STAT3 pathway was of benefit to inhibit angiogenesis and ESCC growth [ 35 , 36 ]. However, our findings indicated that blocking STAT3 might only be applicable to upper ESCC.…”

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia condition

“…Accumulating studies have proved RTKs and their related pathways are frequently dysregulated in OSCC [11,[43][44][45]. IGF1R as a transmembrane glycoprotein and stress-receptor, could feel the stress outside and send these stress signals to intracellular, activating downstream signaling pathways to regulate cell proliferation, migration and chemotherapeutic resistance, etc [12].…”

“…From several recent studies, dysregulated receptor tyrosine kinases (RTKs) family members were found in OSCC patients [10][11]. As"stress-receptors", they can received and transmitted extracellular "harsh" message such as low oxygen to cytoplasm, and started the intracellular downstream signal cascade to cell growth, invasion, metabolism and resistant phenotype of tumor cells [12].…”