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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM)
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From: Icebrg1/24/2007 8:22:00 AM
   of 3044
 
Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib.

Mol Cancer Ther. 2007 Jan;6(1):61-9.

An J, Rettig MB.

VA Greater Los Angeles Healthcare System-West Los Angeles, 11301 Wilshire Boulevard, Building 304, Room E1-113, Los Angeles, CA 90073. matthew.rettig@med.va.gov.

In renal cell carcinoma (RCC) models, maximal cytotoxicity of the proteasome inhibitor bortezomib is dependent on efficient blockade of constitutive nuclear factor kappaB (NF-kappaB) activity. Signaling through the epidermal growth factor receptor (EGFR) has been shown to result in NF-kappaB 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-kappaB 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-kappaB activity. Using pharmacologic and genetic approaches, we also showed that EGFR-mediated NF-kappaB 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-kappaB activity revealed that EGFR-TKI pretreatment markedly augmented the NF-kappaB inhibitory effect of bortezomib, whereas bortezomib preexposure resulted in suboptimal NF-kappaB blockade and thus provides a biochemical explanation for the drug interaction results. We conclude that the constitutive NF-kappaB 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-kappaB activity. The combination of bortezomib and a currently approved EGFR inhibitor warrants clinical investigation. [Mol Cancer Ther 2007;6(1):61-9].
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