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Research Articles: Therapeutics, Targets, and Development

Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib

¹ VA Greater Los Angeles Healthcare System-West Los Angeles and ² David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California

Requests for reprints: Matthew B. Rettig, VA Greater Los Angeles Healthcare System-West Los Angeles, 11301 Wilshire Boulevard, Building 304, Room E1-113, Los Angeles, CA 90073. Phone: 310-268-3622; Fax: 310-268-4508. E-mail: matthew.rettig{at}med.va.gov

Abstract

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

Grant support: Merit Review funds from the Department of Veterans Affairs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/ 8/06; revised 10/21/06; accepted 11/28/06.

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