2. Academic Validation
  3. Blocking STAT3 signaling augments MEK/ERK inhibitor efficacy in esophageal squamous cell carcinoma

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

  • Cell Death Dis. 2022 May 25;13(5):496. doi: 10.1038/s41419-022-04941-3.
Zhen-Yuan Zheng 1 2 3,  Man-Yu Chu 1 2,  Wan Lin 1 2,  Ya-Qi Zheng 1 2,  Xiu-E Xu 1 2,  Yang Chen 1 2,  Lian-Di Liao 1 2,  Zhi-Yong Wu 4,  Shao-Hong Wang 4,  En-Min Li 5 6,  Li-Yan Xu 7 8 9
Affiliations

Affiliations

  • 1 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou University Medical College, Shantou, 515041, Guangdong, China.
  • 3 Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China.
  • 4 Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, 515041, Guangdong, China.
  • 5 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China. nmli@stu.edu.cn.
  • 6 Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China. nmli@stu.edu.cn.
  • 7 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China. lyxu@stu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou University Medical College, Shantou, 515041, Guangdong, China. lyxu@stu.edu.cn.
  • 9 Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China. lyxu@stu.edu.cn.
PMID: 35614034 DOI: 10.1038/s41419-022-04941-3
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.

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