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Feedback activation of EGFR is the main cause for STAT3 inhibition-irresponsiveness in pancreatic cancer cells

Oncogene volume 39, pages 3997–4013 (2020)Cite this article

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Abstract

Pancreatic cancer is one of the world’s leading causes of cancer-related death. Activation of STAT3 has been reported as a major contributor in pancreatic cancer tumorigenesis and chemoresistance. However, treatment of advanced pancreatic cancer patients with STAT3 inhibitors often meets drug resistance and heterogeneous response. We found that EGFR activation is a main cause for resistance to STAT3 inhibitors in pancreatic cancer cells, regardless of KRAS mutation status. Mechanistically, inhibition of STAT3 promotes STAT1- and STAT4-mediated TGF-α expression, leading to activation of the EGFR pathway. Combined treatment of pancreatic cancer cells with EGFR and STAT3 inhibitors persistently blocks EGFR and STAT3 signaling, and exerts synergistic antitumor activity both in vitro and in vivo, with or without KRAS mutation. Our results indicate that reciprocal cross-talk between STAT3 and EGFR pathways is a key molecular mechanism leading to resistance in pancreatic cancer cells. Furthermore, the study shows that combined inhibition of both EGFR and STAT3 might overcome drug resistance encountered during treatment with single agent alone. This study suggests an improved therapeutic strategy, through combined treatment with STAT3 and EGFR inhibitors, for pancreatic cancer patients.

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Fig. 1: Cross-talk between STAT3 and EGFR in drug resistance of pancreatic cancer cells.
Fig. 2: Dual inhibition of EGFR and STAT3 has strong antitumor effects both in vitro and in vivo.
Fig. 3: Synthesis and screening of new STAT3 small-molecule inhibitors.
Fig. 4: Synergistic inhibition of cell viability by newly synthesized STAT3 small-molecule inhibitors and EGFR/ERK inhibitors.
Fig. 5: Newly synthesized STAT3 small-molecule inhibitors sensitize human pancreatic cancer cells to EGFR/MEK inhibitors in vivo.
Fig. 6: TGF-α is responsible for increased EGFR phosphorylation upon STAT3 inhibition.
Fig. 7: STAT1 and STAT4 is responsible for STAT3 inhibition induced TGF-α expression.

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Acknowledgements

This research was supported by National Natural Science Foundation of China (81672305 and 81773579), Natural Science Foundation of Zhejiang Province (LY17B020008 and LY18H160047), Medical Scientific Research Fund of Zhejiang Province (2019322308) and Wenzhou science and technology project (Y20190179).

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  1. These authors contribute equally: Chengguang Zhao, Lehe Yang, Feng Zhou

Authors and Affiliations

  1. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Chengguang Zhao, Lehe Yang, Feng Zhou, Yun Yu, Zhiguo Liu, Guang Liang & Ri Cui

  2. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

    Chengguang Zhao, Lehe Yang, Feng Zhou, Xiaojing Du, Youqun Xiang, Xiaoying Huang, Congying Xie, Zhiguo Liu, Liangxing Wang & Ri Cui

  3. Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, Zhejiang, China

    Chengguang Zhao, Guang Liang & Ri Cui

  4. Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA

    Lehe Yang & Jiayuh Lin

  5. College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA

    Chenglong Li

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Contributions

CZ, RC, and LW conceived the idea and designed the research. LY, FZ, YY, and XD performed in vitro experiments. CZ, LY, FZ, YX, and XD performed mice xenograft experiments. CL and ZL designed and synthesized new compounds 1–8. GL, XH, CX, CZ, and RC analyzed the data. RC, CZ, and JL wrote the paper.

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Correspondence to Liangxing Wang, Guang Liang or Ri Cui.

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Zhao, C., Yang, L., Zhou, F. et al. Feedback activation of EGFR is the main cause for STAT3 inhibition-irresponsiveness in pancreatic cancer cells. Oncogene 39, 3997–4013 (2020). https://doi.org/10.1038/s41388-020-1271-y

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