Glioblastoma-derived epidermal growth factor receptor carboxyl-terminal deletion mutants are transforming and are sensitive to EGFR-directed therapies
Authors: Jeonghee Cho
Jihyun Kwon
Qing Zeng
Scott Vandenberg
Sandra Pastorino
Matthew Meyerson
Xiaoyin Xu
Roel Verhaak
Yuki Yuza
Ying S Chao
Andrew D Cherniack
William Johnson
Derek Chiang
Hideo Watanabe
Santosh Kesari
Amit Dutt
Robert C Onofrio
Journal: Cancer research (2011)
Discipline: CLINICAL MEDICINE
Keywords: EGFR; genomic alterations; glioblastoma multiforme; exon 27 deletion mutation; carboxyl-terminus domain
Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Abstract:  Genomic alterations of the epidermal growth factor receptor (EGFR) gene play a crucial role in pathogenesis of glioblastoma multiforme (GBM). By systematic analysis of GBM genomic data, we have identified and characterized a novel exon 27 deletion mutation occurring within the EGFR carboxyl-terminus domain (CTD), in addition to identifying additional examples of previously reported deletion mutations in this region. We show that the GBM-derived EGFR CTD deletion mutants are able to induce cellular transformation in vitro and in vivo in the absence of ligand and receptor autophosphorylation. Treatment with the EGFR-targeted monoclonal antibody, cetuximab, or the small molecule EGFR inhibitor, erlotinib, effectively impaired tumorigenicity of oncogenic EGFR CTD deletion mutants. Cetuximab in particular prolonged the survival of intracranially xenografted mice with oncogenic EGFR CTD deletion mutants, compared with untreated control mice. Therefore, we propose that erlotinib and, especially, cetuximab treatment may be a promising therapeutic strategy in GBM patients harboring EGFR CTD deletion mutants. 

Retracted: No

PubPeer comments:
 ![file] , 
 ![file] I have attached a screenshot from our original image file. As I see them, these images are not identical but show several clear distinctions. First, there are cells that stain with the anti-EGFR antibody (top image in the attachment) but do not stain with the antibody directed against EGFR with phosphorylated Tyr-1197 (bottom image). Second, in this higher-resolution image, it can be seen that for the cells that are stained with both antibodies, the relative intensities of the staining, at different locations, are different. Third, you will notice that the shapes of the cells and structures are quite similar, but are different. There appear to be a small number of cells or cell protrusions (hard to tell which at this resolution) that are present in one of the two images but not the other image. I also down-loaded a fresh copy of the manuscript from Cancer Research for comparison. The down-loaded version has significantly decreased figure resolution--the images look pixelated to me. I think that this is is what makes the images more similar to one another, as in your screen shot that you showed.. The attached image still doesn t have great resolution, so I will try to get higher resolution images for you soon. Also, I will check the printed version of the paper, probably next week, to see if the image issues are also in the print version or if the images are clear there. , 
 Before we go too far, is it possible that what one has here are successive serial sections? The top right most panel (H E, CT Del1) is also similar (grossly) to the lower two panels, though the lower two are much more similar to each other; they nonetheless have distinct differences. So if these are successive sections through tissue, isn t this what one might expect? I see the same sort of pattern in the first column of pictures (WT EGFR), though these three pictures are distinct from one another. , 
 I agree, isn t this a good thing? They used adjacent sections to stain for different proteins allowing a valid and appropriate comparison. I m not sure why this was raised in the first place, there are clear differences (i.e they are not identical) and if Bonellia Viridis had actually bothered to read the paper and understand the science, it would have been obvious what the authors were doing. ,