PMID- 30585254 OWN - NLM STAT- MEDLINE DCOM- 20191112 LR - 20211204 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 120 IP - 3 DP - 2019 Feb TI - Co-targeting EGFR and IKKbeta/NF-kappaB signalling pathways in head and neck squamous cell carcinoma: a potential novel therapy for head and neck squamous cell cancer. PG - 306-316 LID - 10.1038/s41416-018-0351-z [doi] AB - BACKGROUND: Epidermal growth factor receptor (EGFR) plays an important role in head and neck squamous cell carcinoma (HNSCC) proliferation and therapy resistance, but the efficacy of targeting of EGFR for therapy has been limited. Here, we explore the molecular link between EGFR and inhibitor of kappaB kinase beta/nuclear factor-kappaB (IKKbeta/NF-kappaB) signalling pathways in the regulation of HNSCC EGFR inhibitor resistance. METHODS: We performed in vitro experiments in eight human HNSCC cell lines and a patient-derived HNSCC cell line as well as in vivo xenografts in a human HNSCC cell line. RESULTS: We found that treatment of all HNSCC cells with Gefitinib and Erlotinib, two Food Drug Administration-approved EGFR inhibitors, blocked the activity of Akt/mammalian target of the rapamycin (mTOR) and extracellular signal-regulated kinase, two crucial downstream effectors of EGFR, but up-regulated IKKbeta/NF-kappaB signalling. In addition, induction of IKKbeta/NF-kappaB by EGFR inhibitors required HER2 and HER3 expression. In keeping with these, IKKbeta inhibitor CmpdA synergistically enhanced the efficacy of EGFR inhibitors to further inhibit in vitro HNSCC cell growth. Importantly, we demonstrated that the combination of Gefitinib with CmpdA inhibited xenograft tumour formation. CONCLUSION: Our data demonstrated that co-targeting EGFR and IKKbeta with Gefitinib and IKKbeta inhibitors could provide a potential novel therapy for head and neck squamous cell cancer. FAU - Li, Zhipeng AU - Li Z AD - Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Liao, Jipei AU - Liao J AD - Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Yang, Zejia AU - Yang Z AD - Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Choi, Eun Yong AU - Choi EY AD - Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Lapidus, Rena G AU - Lapidus RG AD - Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Liu, Xuefeng AU - Liu X AD - Department of Pathology, Georgetown University Medical Center, Washington, DC, USA. FAU - Cullen, Kevin J AU - Cullen KJ AD - Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Dan, Hancai AU - Dan H AD - Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. HDan@som.umaryland.edu. AD - Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA. HDan@som.umaryland.edu. LA - eng GR - R00 CA149178/CA/NCI NIH HHS/United States GR - R01 CA212094/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181226 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Bay 65-1942) RN - 0 (NF-kappa B) RN - 0 (Oxazines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - DA87705X9K (Erlotinib Hydrochloride) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.10 (I-kappa B Kinase) RN - S65743JHBS (Gefitinib) SB - IM MH - Animals MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Drug Resistance, Neoplasm/drug effects MH - ErbB Receptors/antagonists & inhibitors/genetics MH - Erlotinib Hydrochloride/administration & dosage MH - Gefitinib/administration & dosage MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - I-kappa B Kinase/antagonists & inhibitors/*genetics MH - Mice MH - NF-kappa B/genetics MH - Oxazines/pharmacology/*therapeutic use MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects MH - Pyridines/pharmacology/*therapeutic use MH - Receptor, ErbB-2/genetics MH - Receptor, ErbB-3/genetics MH - Signal Transduction/drug effects MH - Squamous Cell Carcinoma of Head and Neck/*drug therapy/genetics/pathology MH - TOR Serine-Threonine Kinases/genetics MH - Xenograft Model Antitumor Assays PMC - PMC6353914 COIS- The authors declare no competing interests. EDAT- 2018/12/27 06:00 MHDA- 2019/11/13 06:00 PMCR- 2019/12/26 CRDT- 2018/12/27 06:00 PHST- 2018/03/23 00:00 [received] PHST- 2018/11/14 00:00 [accepted] PHST- 2018/10/18 00:00 [revised] PHST- 2018/12/27 06:00 [pubmed] PHST- 2019/11/13 06:00 [medline] PHST- 2018/12/27 06:00 [entrez] PHST- 2019/12/26 00:00 [pmc-release] AID - 10.1038/s41416-018-0351-z [pii] AID - 351 [pii] AID - 10.1038/s41416-018-0351-z [doi] PST - ppublish SO - Br J Cancer. 2019 Feb;120(3):306-316. doi: 10.1038/s41416-018-0351-z. Epub 2018 Dec 26.