title: Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib.
abstract: 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.
authors.affiliation: VA Greater Los Angeles Healthcare System-West Los Angeles, 11301 Wilshire Boulevard, Building 304, Room E1-113, Los Angeles, CA 90073, USA.
authors.forename: Jiabin
authors.initials: J
authors.lastname: An
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Rettig
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D000069286:Bortezomib; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004334:Drug Administration Schedule; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D011799:Quinazolines; D000069286:Bortezomib; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline