Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma
| Autor: | R M Bukowski, M Zhou, Robert M. Gemmill, Luciano J. Costa, Christopher Korch, Harry A. Drabkin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
medicine.medical_treatment protein biosynthesis Ubiquitin-Protein Ligases Antineoplastic Agents urologic and male genital diseases Cell Line 03 medical and health sciences 0302 clinical medicine Growth factor receptor Cell Line Tumor medicine Humans Epidermal growth factor receptor Protein kinase B neoplasms Carcinoma Renal Cell PI3K/AKT/mTOR pathway 030304 developmental biology EGFR inhibitors Sirolimus 0303 health sciences biology Growth factor TOR Serine-Threonine Kinases Tumor Suppressor Proteins Genetics and Genomics Drug Synergism Gefitinib female genital diseases and pregnancy complications Kidney Neoplasms ErbB Receptors Oncology Polysome binding Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis mitogen-activated protein kinases Mutation Cancer research biology.protein Quinazolines epidermal growth factor receptor Protein Kinases medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFalpha) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel-Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHL-dependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated post-transcriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation. |
| Databáze: | OpenAIRE |
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