Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non-Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling.

Abstract

Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified.Experimental Design: AhR expression in non-small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms.Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2-Src interaction, which does not require the canonical transcriptional activity of AhR.Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC. Clin Cancer Res; 24(5); 1227-39. ©2017 AACR.

• Authors: Mingxiang Ye, Yong Zhang, Hongjun Gao, Yan Xu, Pengyu Jing, Jianxiong Wu, Xinxin Zhang, Jie Xiong, Chenfang Dong, Libo Yao, Jian Zhang, Jian Zhang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 5 Pg. 1227-1239 (03 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29229632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• AHR protein, human
• Basic Helix-Loop-Helix Transcription Factors
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Receptors, Aryl Hydrocarbon
• EGFR protein, human
• ErbB Receptors
• JAK2 protein, human
• Janus Kinase 2
• src-Family Kinases

Topics

• Adult
• Aged
• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, mortality, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Female
• Follow-Up Studies
• Humans
• Janus Kinase 2 (genetics, metabolism)
• Lung Neoplasms (drug therapy, mortality, pathology)
• Male
• Mice, Nude
• Middle Aged
• Mutation
• Prognosis
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• RNA, Small Interfering (metabolism)
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays
• src-Family Kinases (genetics, metabolism)