title: MEK inhibitor PD-0325901 overcomes resistance to CK2 inhibitor CX-4945 and exhibits anti-tumor activity in head and neck cancer.
abstract: The serine-threonine kinase CK2 exhibits genomic alterations and aberrant overexpression in human head and neck squamous cell carcinomas (HNSCC). Here, we investigated the effects of CK2 inhibitor CX-4945 in human HNSCC cell lines and xenograft models. The IC50's of CX-4945 for 9 UM-SCC cell lines measured by MTT assay ranged from 3.4-11.9 μM. CX-4945 induced cell cycle arrest and cell death measured by DNA flow cytometry, and inhibited prosurvival mediators phospho-AKT and p-S6 in UM-SCC1 and UM-SCC46 cells. CX-4945 decreased NF-κB and Bcl-XL reporter gene activities in both cell lines, but upregulated proapoptotic TP53 and p21 reporter activities, and induced phospho-ERK, AP-1, and IL-8 activity in UM-SCC1 cells. CX-4945 exhibited modest anti-tumor activity in UM-SCC1 xenografts. Tumor immunostaining revealed significant inhibition of PI3K-Akt-mTOR pathway and increased apoptosis marker TUNEL, but also induced p-ERK, c-JUN, JUNB, FOSL1 and proliferation (Ki67) markers, as a possible resistance mechanism. To overcome the drug resistance, we tested MEK inhibitor PD-0325901 (PD-901), which inhibited ERK-AP-1 activation alone and in combination with CX-4945. PD-901 alone displayed significant anti-tumor effects in vivo, and the combination of PD-901 and CX-4945 slightly enhanced anti-tumor activity when compared with PD-901 alone. Immunostaining of tumor specimens after treatment revealed inhibition of p-AKT S129 and p-AKT T308 by CX-4945, and inhibition of p-ERK T202/204 and AP-1 family member FOSL-1 by PD-901. Our study reveals a drug resistance mechanism mediated by the MEK-ERK-AP-1 pathway in HNSCC. MEK inhibitor PD-0325901 is active in HNSCC resistant to CX-4945, meriting further clinical investigation.
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA;
authors: Yansong
authors: Y
authors: Bian
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA; ; 2. Department of Otolaryngology Head and Neck Surgery, National Key Discipline, Key Laboratory of Otolaryngology Head and Neck Surgery of the Ministry of Education, Beijing Tongren Hospital, Capital Medical University, Beijing, China;
authors: Jiawei
authors: J
authors: Han
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA; ; 3. NIH Clinical Research Training Program-NIH Medical Research Scholars Program, Bethesda, MD, USA.
authors: Vishnu
authors: V
authors: Kannabiran
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA; ; 3. NIH Clinical Research Training Program-NIH Medical Research Scholars Program, Bethesda, MD, USA.
authors: Suresh
authors: S
authors: Mohan
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA;
authors: Hui
authors: H
authors: Cheng
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA;
authors: Jay
authors: J
authors: Friedman
authors: 2. Department of Otolaryngology Head and Neck Surgery, National Key Discipline, Key Laboratory of Otolaryngology Head and Neck Surgery of the Ministry of Education, Beijing Tongren Hospital, Capital Medical University, Beijing, China;
authors: Luo
authors: L
authors: Zhang
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA;
authors: Carter
authors: C
authors: VanWaes
authors: 1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA;
authors: Zhong
authors: Z
authors: Chen
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009287:Naphthyridines / Q000627:therapeutic use*; D010619:Phenazines; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099169:Fos-Related Antigen 1
chemical_list: D001549:Benzamides; D047390:Casein Kinase II; D004159:Diphenylamine; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009287:Naphthyridines; D010619:Phenazines; D016760:Proto-Oncogene Proteins c-fos; D016159:Tumor Suppressor Protein p53; D000099169:Fos-Related Antigen 1; C506614:mirdametinib; C555142:silmitasertib
keywords: CK2 inhibitor; CX-4945; MEK inhibitor; PD-0325901; head and neck cancer.