4.8 Article

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

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NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27276-7

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资金

  1. Department of Veteran's Affairs [2I01BX002559-07]
  2. National Institutes of Health [1R01CA24421201A1, RO1CA197796]
  3. NCI Lung Cancer SPORE [P50CA70907, U01CA176284]
  4. CPRIT [RP110708, RP160652, RR160080]
  5. National Cancer Institute (NCI) Midcareer Investigator Award in Patient-Oriented Research [K24CA201543-01]
  6. National Aeronautics and Space Administration [NNX16AD78G]
  7. NCI [2P50CA070907-22]
  8. Welch Foundation [1975-20190330]
  9. A Breath of Hope Lung Foundation Fellowship Award (ABOHLF 2020)
  10. NCCN Foundation Young Investigator Award (NCCN 2021)
  11. Forbeck Foundation
  12. NIH [R01 CA194578, 1S10OD023552-01]
  13. Harold C. Simmons Comprehensive Cancer Center's Biomarker Research Core - NCI Cancer Center Support Grant [1P30 CA142543-03]

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The study explored the efficacy of broad versus focused targeting of resistance to EGFR inhibition in NSCLC, finding that a broad inhibitor of inflammation, prednisone, is the most effective in suppressing inflammatory signals and resistance mechanisms.
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-kappa B. 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. TNF signalling was reported to mediate resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Here, the authors examine the efficacy of a broad versus focused targeting of this resistance, and they show that a broad inhibitor of inflammation, prednisone is the most effective.

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