In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2808-2808
Abstract:
In this study, we employed a novel integrative genomic-based approach to explore driving gene fusions contributing to the progression of advanced prostate cancer. This method, called amplification breakpoint ranking and assembly (ABRA), leverages the in vivo amplification and breakpoint analysis in cancer cells to assemble novel gene fusions and predict their tumorigenicity. Using ABRA, we nominated KRAS as a gene fusion with the ubiquitin-conjugating enzyme UBE2L3 in the DU145 cell line- which was originally derived from a metastatic prostate cancer to the brain. Interestingly, analysis of tissues revealed that 2 out of 62 metastatic prostate cancers harbored aberrations at the KRAS locus. In DU145 cells, UBE2L3-KRAS produces a chimerical protein which is readily ubiquitinated and relative instable, whereas specific knock-down of the fusion attenuates cell invasion and xenograft growth. Further, ectopic expression of the UBE2L3-KRAS fusion protein in NIH 3T3 fibroblasts and RWPE prostate epithelial cells exhibits substantial transforming activity in vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates the MEK/ERK pathway, which is commonly engaged by oncogenic mutant KRAS. Instead, it enriches Ras proteins in late endosome, and diverts signaling to the AKT and p38 MAPK pathways. While a number of oncogenic activating point mutations of KRAS have been identified, this is the first description of a mutant chimeric version of KRAS that is oncogenic and thus may represent a new class of cancer-related alteration. This study also suggests that this aberration may drive metastatic progression in a subset of prostate cancers, which may be targeted by anti-KRAS therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2808. doi:10.1158/1538-7445.AM2011-2808
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-2808
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
