Inhibition of NF-κB improves sensitivity to irradiation and EGFR-TKIs and decreases irradiation-induced lung toxicity.

Abstract

Resistance to radiotherapy and to EGFR tyrosine kinase inhibitors (EGFR-TKIs), as well as therapy-related lung toxicity, are serious problems in the treatment of lung cancer. NF-κB has been reported to be associated with radioresistance. Therefore, we evaluated its effects on sensitivity to irradiation and to EGFR-TKIs; irradiation-induced lung toxicity; and the effects of irradiation on sensitivity to EGFR-TKIs. We used IKKβ inhibitor IMD 0354 or p65 depletion to explore their effects on sensitivity to irradiation and to EGFR-TKIs in vitro and in vivo. We evaluated the efficacy of IMD 0354 in a radiation-induced pulmonary-fibrosis mouse model. Irradiation enhanced activation and expression of MET and therefore suppressed the sensitivity of lung cancer cells to irradiation or EGFR-TKIs. Inhibition of NF-κB by IMD 0354 or by p65 depletion reversed irradiation-induced MET activation and increased the sensitivity of lung cancer cells to irradiation, to EGFR-TKIs and to the combination thereof in vitro and in vivo. In addition, IMD 0354 significantly reduced lung toxicity in a murine model of irradiation-induced pneumonia and lung fibrosis. These findings indicated that NF-κB inhibition can improve sensitivity to irradiation and to EGFR-TKIs and can decrease irradiation-induced lung toxicity in lung cancer.

• Authors: Rong Wang, Shunli Peng, Xiaojuan Zhang, Zhenming Wu, Hezhen Duan, Yawei Yuan, Wei Wang
• Journal: International journal of cancer (Int J Cancer) Vol. 144 Issue 1 Pg. 200-209 (01 01 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30289964 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 UICC.

Chemical References

• Benzamides
• NF-kappa B
• Protein Kinase Inhibitors
• N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
• EGFR protein, human
• ErbB Receptors

Topics

• A549 Cells
• Animals
• Benzamides (pharmacology)
• Cell Line
• Cell Line, Tumor
• Chemoradiotherapy (methods)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Lung (drug effects, pathology, radiation effects)
• Lung Neoplasms (therapy)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Radiation Tolerance (drug effects)
• Tumor Burden (drug effects, radiation effects)
• Xenograft Model Antitumor Assays