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

Ke Gong, Gao Guo, Nicole A. Beckley, Xiaoyao Yang, Yue Zhang, David E. Gerber, John D. Minna, Sandeep Burma, Dawen Zhao, Esra A. Akbay and Amyn A. Habib ()
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Ke Gong: University of Texas Southwestern Medical Center
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
John D. Minna: University of Texas Southwestern Medical Center
Sandeep Burma: 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

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27276-7

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