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Sub-category:
Melanoma
Category:
Melanoma
Meeting:
2008 ASCO Annual Meeting
Abstract No:
9019
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 9019)
Author(s):
K. O'Reilly, M. A. Warycha, M. Davies, X. K. Zhou, H. Yee, N. Bhardwaj, A. C. Pavlick, G. B. Mills, N. Rosen, I. Osman
Abstract:
Background: Both the PI3K/AKT and RAS/MAPK signal transduction pathways mediate 4EBP1 phosphorylation, releasing 4EBP1 from the mRNA cap and permitting translation initiation. Given the high frequency of mutations in BRAF and PTEN in melanoma, we hypothesized that translation initiation, as measured by phosphorylated 4EBP1 (p-4EBP1), would be enhanced in metastatic melanoma and associated with worse survival. Methods: Human melanoma cell lines characterized for PTEN, BRAF, and NRAS mutational status (n=7) were studied for total 4EBP1 and p-4EBP1 by western blotting. 81 metastatic melanomas from 76 patients, were examined for 4EBP1 and p-4EBP1 expression using immunohistochemistry. In a subset of these patients (n=38), we measured 4EBP1 transcript using Affymetrix microarray and 4EBP1 and p-4EBP1 levels with reverse phase protein array (RPPA). We correlated protein expression of total and p-4EBP1, transcript expression, and RPPA expression levels with survival using the Cox proportional hazard model. Results: Total 4EBP1 was strongly expressed and hyperphosphorylated in 4/7 (57%) melanoma cell lines with NRAS or B-RAF and/or PTEN mutations as compared to cultured melanocytes or a wild type melanoma line. p-4EBP1 T70 was positive in 74% of metastatic melanomas and associated with worse overall and post-recurrence survival (HR= 2.32, 3.86 p=0.033, 0.009, respectively). 4EBP1 transcript was also associated with worse overall and post-recurrence survival (HR= 1.84, 2.16 p=0.031, 0.002, respectively). RPPA analysis allowed detection of multiple 4EBP1 phosphorylation sites in the same samples, with p-4EBP1 T70 RPPA levels strongly correlated with RPPA levels of 4EBP1 phosphorylated at sites T37/T46 (r=0.76). Conclusions: We demonstrate that deregulation of translation initiation is a common biologic event in metastatic melanoma and correlates with worse survival. Our data suggest that dephosphorylation of 4EBP1 via inhibition of the pathways responsible for 4EBP1 phosphorylation might represent a rational, novel strategy for treatment of metastatic melanoma.
Abstract Disclosures
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy
and are designated with a caret symbol (^) here and in the print version.
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