MEK inhibitor PD-0325901 overcomes resistance to CK2 inhibitor CX-4945 and exhibits anti-tumor activity in head and neck cancer

Int J Biol Sci. 2015 Feb 23;11(4):411-22. doi: 10.7150/ijbs.10745. eCollection 2015.

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.

Keywords: CK2 inhibitor; CX-4945; MEK inhibitor; PD-0325901; head and neck cancer..

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Benzamides / therapeutic use*
  • Blotting, Western
  • Casein Kinase II / antagonists & inhibitors
  • Cell Line, Tumor
  • Diphenylamine / analogs & derivatives*
  • Diphenylamine / therapeutic use
  • Female
  • Flow Cytometry
  • Head and Neck Neoplasms / drug therapy*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • NF-kappa B / metabolism
  • Naphthyridines / therapeutic use*
  • Phenazines
  • Proto-Oncogene Proteins c-fos / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Benzamides
  • NF-kappa B
  • Naphthyridines
  • Phenazines
  • Proto-Oncogene Proteins c-fos
  • Tumor Suppressor Protein p53
  • fos-related antigen 1
  • mirdametinib
  • Diphenylamine
  • silmitasertib
  • Casein Kinase II
  • JNK Mitogen-Activated Protein Kinases