An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice

作者：Gronych Jan; Korshunov Andrey; Bageritz Josephine; Milde Till; Jugold Manfred; Hambardzumyan Dolores; Remke Marc; Hartmann Christian; Witt Hendrik; Jones David T W; Witt Olaf; Heiland Sabine; Bendszus Martin; Holland Eric C; Pfister Stefan; Lichter Peter^*

来源：Journal of Clinical Investigation, 2011, 121(4): 1344-1348.

DOI：10.1172/JCI144656

Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.

• 出版日期2011-4