Journal
MOLECULAR CANCER THERAPEUTICS
Volume 6, Issue 1, Pages 61-69Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-06-0255
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In renal cell carcinoma (RCC) models, maximal cytotoxicity of the proteasome inhibitor bortezomib is dependent on efficient blockade of constitutive nuclear factor KB (NF-KB) activity. Signaling through the epidermal growth factor receptor (EGFR) has been shown to result in NF-KB activation. Thus, we sought to investigate whether inhibition of the EGFR sensitizes RCC cells to the cytotoxic effects of bortezomib. We first established that constitutive NF-KB activity is dependent on signaling through the EGFR in RCC cells. Indeed, blockade of EGFR signaling with an EGFR tyrosine kinase inhibitor (TKI) resulted in inhibition of NF-KB activity. Using pharmacologic and genetic approaches, we also showed that EGFR-mediated NF-KB activation occurs through the phosphotidylinositol-3-OH kinase/AKT pathway. Combinations of the EGFR-TKI and bortezomib resulted in synergistic cytotoxic effects when RCC cells were pretreated with the EGFR-TKI, but an antagonistic interaction was observed with bortezomib pretreatment. Evaluation of the effects of drug sequencing on inhibition of NF-KB activity revealed that EGFR-TKI pretreatment markedly augmented the NF-KB inhibitory effect of bortezomib, whereas bortezomib preexposure resulted in suboptimal NF-KB blockade and thus provides a biochemical explanation for the drug interaction results. We conclude that the constitutive NF-KB activity observed in RCC cells is mediated, at least in part, through an EGFR/phosphotidylinositol-3-OH kinase/AKT signaling cascade. Pretreatment with an EGFR-TKI sensitizes to bortezomib-mediated cytotoxicity by inhibiting constitutive NF-KB activity. The combination of bortezomib and a currently approved EGFR inhibitor warrants clinical investigation.
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