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Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids

Author

Listed:
  • Ke Gong

    (University of Texas Southwestern Medical Center
    Wuhan University)

  • Gao Guo

    (University of Texas Southwestern Medical Center)

  • Nicole A. Beckley

    (University of Texas Southwestern Medical Center)

  • Xiaoyao Yang

    (University of Texas Southwestern Medical Center)

  • Yue Zhang

    (University of Texas Southwestern Medical Center)

  • David E. Gerber

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • John D. Minna

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Sandeep Burma

    (University of Texas Health San Antonio
    University of Texas Health San Antonio)

  • Dawen Zhao

    (Wake Forest School of Medicine)

  • Esra A. Akbay

    (University of Texas Southwestern Medical Center)

  • Amyn A. Habib

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    VA North Texas Health Care System)

Abstract

Inhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers.

Suggested Citation

  • Ke Gong & Gao Guo & Nicole A. Beckley & Xiaoyao Yang & Yue Zhang & David E. Gerber & John D. Minna & Sandeep Burma & Dawen Zhao & Esra A. Akbay & Amyn A. Habib, 2021. "Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27276-7
    DOI: 10.1038/s41467-021-27276-7
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    1. Timothy R. Wilson & Jane Fridlyand & Yibing Yan & Elicia Penuel & Luciana Burton & Emily Chan & Jing Peng & Eva Lin & Yulei Wang & Jeff Sosman & Antoni Ribas & Jiang Li & John Moffat & Daniel P. Suthe, 2012. "Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors," Nature, Nature, vol. 487(7408), pages 505-509, July.
    2. Rui Hou & Elena Denisenko & Huan Ting Ong & Jordan A. Ramilowski & Alistair R. R. Forrest, 2020. "Predicting cell-to-cell communication networks using NATMI," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Anirudh Prahallad & Chong Sun & Sidong Huang & Federica Di Nicolantonio & Ramon Salazar & Davide Zecchin & Roderick L. Beijersbergen & Alberto Bardelli & René Bernards, 2012. "Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR," Nature, Nature, vol. 483(7387), pages 100-103, March.
    4. Sharmistha Chakraborty & Li Li & Vineshkumar Thidil Puliyappadamba & Gao Guo & Kimmo J. Hatanpaa & Bruce Mickey & Rhonda F. Souza & Peggy Vo & Joachim Herz & Mei-Ru Chen & David A. Boothman & Tej K. P, 2014. "Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks," Nature Communications, Nature, vol. 5(1), pages 1-15, December.
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