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Alternative functions of K-RAS in endocrine tumors

 

The genetic control of endocrine tumors development are often related with oncogenes in other tumor types, due to the response of endocrine tumors to the hormone related signals. As in the pancreas, the activating mutation of K-RAS promotes proliferation of pancreatic ductal adenocarcinomas, but absents in pancreatic endocrine tumors, indicating that K-RAS may function in a context-dependent manner. Chamberlian et al. found K-RAS suppresses the growth in pancreatic endocrine cells, in contrast to its promoting effect on other cancer cells. The article was published in The Journal of Clinical Investigation.

 

In pancreatic endocrine tumors, the inactivation of tumor suppressors is often happened, including menin, which inhibits multiple endocrine neoplasia type 1 (MEN1), as well as RASSF1A, which is an antiproliferative effector of activated K-RAS. Researchers found the inactivation of these two suppressors is critical for the alternative functions of K-RAS signaling. Mechanically, loss of menin promotes proliferation of cells by increasing MAPK-driven proliferation downstream of K-RAS signaling, meanwhile, the loss of K-RAS signaling promotes proliferation by down-regulating RASSF1A activity. Consistently, in combination with a menin inhibitor, a ERK1/2 phosphorylation stimulator, glucangon-like peptide 1 (GLP1) agonist, enhanced proliferation of endocrine cells. The results provides a potential strategies for menin-sensitive endocrine tumors.

 

Reference:
J Clin Invest. 2014 Sep 2;124(9):4093-101.

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