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MAPKAP kinase 2 overexpression influences prognosis in gastrointestinal stromal tumors

2/23/2012

PREFACE FROM MARINA


Here's a new an interesting science paper about GIST, which ties into another very interesting science paper about GIST, KIT, and a nuclear transcription factor called ETV1 by Charles Sawyers lab last year. (Charles Sawyers was a pioneer with Druker of TKI treatments for CML.)

Researchers in Austria claim that a regulatory protein called MAPKAP kinase 2 is overexpressed and sometimes damaged by mutation in GIST. MAPKAP kinase 2 protein inhibits the activity of ETV1, a transcription factor that Sawyers's lab identified as an essential and necessary downstream mediator of the signals from mutant KIT. This new abstract claims that mutants in the MAPKAP kinase 2 gene are found in "low risk GISTs" that relapse.

These authors believe MAPKAP kinase 2 is the more relevant culprit in GIST compared to ETV1. Since science is usually an interative process of back and forth of ideas and data that may take years or longer, we can expect other researchers to collect more data of their own and add their own interpretations, which may contradict or confirm these earlier papers. Such is how science works. We have to wait by the sidelines.

The authors mention drugs that inhibit MAPKAP kinase 2 are under development. The authors received a grant from Pfizer for this work. I noticed from Google that Pfizer has MAPKAP 2 kinase inhibitors under development, as this target has been identified as relevant in inflammatory diseases.

Usually basic science findings take years and years (if indeed ever) to pan out into anything patients might use in the clinic. Keep that mind, and don't start planning ahead that any basic finding will be relevant to your case specifically. Still, it's nice to look forward to the frontiers of what is known.


http://www.ncbi.nlm.nih.gov/pubmed/22351694

Clin Cancer Res. 2012 Feb 20. [Epub ahead of print] MAPKAP kinase 2 overexpression influences prognosis in gastrointestinal stroma tumors, associates with copy number variations on chromosome 1, and expression of p38 MAP kinase and ETV1. Birner P, Beer A, Vinatzer U, Stary S, Hoftberger R, Nirtl N, Wrba F, Streubel B, Schoppmann SF. Source

Clinical Institute of Pathology, Medical University of Vienna. Abstract PURPOSE:

ETV1 has been proposed to be activated by KIT-mutations in gastrointestinal stromal tumors (GISTs). Aim of the study was to evaluate the clinical role of ETV1 and associated proteins in GIST.Experimental design: Expressions of ETV1, MAPKAP kinase 2 (MAPKAPK2), phosphorylated p38 MAP kinase (pp38), phosphorylated MSK1 (pMSK1), phosphorylated RSK1, COP1 and KIT protein were determined immunohistochemically in 139 GISTs. Sequence analysis of KIT, PDGFRA and MAPKAPK2 and fluorescence in situ hybridizations of ETV1 as well as chromosomes 1 and 7 were performed. RESULTS:

Prominent ETV1 expression was seen in 50% of GISTs, but no correlation with clinical outcome was found. Correlation of ETV1 expression and KIT mutation was seen in 60% of cases. MAPKAPK2 overexpression (n=62/ 44.6%) correlated with pp38 expression (p=0.021, Chi Square test) and alterations of chromosome 1 (n=17, p=0.024, Chi Square test). In one of 20 sequenced cases with high MAKAPK2 expression, a putative damaging MAPKAPK2 gene mutation was found. All relapsing GISTs with very low/low risk according to Fletcher showed high MAPKAPK2 and KIT expression. MAPKAPK2 overexpression was an independent prognostic factor for disease free survival (p=0.006, Cox regression). CONCLUSION:

ETV1 is not universally overexpressed in GIST and seems to be induced also by other pathways than KIT-mutation. Nevertheless, its clinical relevance is low. Overexpression of ETV1 inhibitor MAPKAPK2 is associated with shorter survival in GIST, indicating a clinical relevant role of this gene not reported previously. Patients with low risk GISTs showing MAPKAPK2 overexpression might profit from early adjuvant tyrosine kinase inhibitor therapy.

PMID:

   22351694
   [PubMed - as supplied by publisher]