FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-kappaB.

ABSTRACT: Quinacrine, a drug with antimalarial and anticancer activities that inhibits NF-κB and activates p53, has progressed into phase II clinical trials in cancer. To further elucidate its mechanism of action and identify pathways of drug resistance, we used an unbiased method for validation-based insertional mutagenesis to isolate a quinacrine-resistant cell line in which an inserted CMV promoter drives overexpression of the FER tyrosine kinase (FER). Overexpression of FER from a cDNA confers quinacrine resistance to several different types of cancer cell lines. We show that quinacrine kills cancer cells primarily by inhibiting the activation of NF-κB and that increased activation of NF-κB through FER overexpression mediates resistance. EGF activates NF-κB and stimulates phosphorylation of FER,

SUBMITTER: Guo C 

PROVIDER: S-EPMC3093511 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature