Abstract A185: Menin functions as a gatekeeper of the proliferative MAPK arm of K-Ras signaling.

Abstract

Abstract Activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas, but have never been found in pancreatic endocrine tumors, which more commonly inactivate tumor suppressors such as MEN1, the gene mutated in the autosomal dominant cancer syndrome Multiple Endocrine Neoplasia type 1, showing that outcomes of K-Ras signaling depend on cellular context. We have shown that K-Ras does not promote but instead strongly suppresses endocrine cell growth and that this paradoxical activity derives from the Men1 gene product Menin. We have proposed a model in which K-Ras activates both the pro-proliferative MAPK pathway, and the anti-proliferative RASSF1 pathway. In tissues susceptible to MEN1 gene mutation, Menin normally prevents the MAPK effector pathway from driving proliferation while leaving the inhibitory RASSF1 effector pathway intact. In this model, loss of Menin causes proliferation due to removal of the block in MAPK-driven proliferation downstream of K-Ras, while loss of K-Ras signaling increases proliferation by decreasing the unopposed RASSF1 activity in susceptible cells. To test this model, we assessed the effect of various inhibitors of the K-Ras pathway on beta cell proliferation in cultured mouse islets. We found that treatment with a combination of farnesyl- and geranyl-geranyl-transferase inhibitors, which block K-Ras signaling, stimulated beta cell proliferation; but blocking MAPK signaling with an inhibitor of Mek1/2 had no effect on proliferation rate. However, in beta-cells with reduced Men1 gene dosage, both K-Ras and Mek1/2 inhibition reduced the increased basal replication rate, consistent with our model that Menin specifically blocks pro-proliferative outputs of the MAPK arm of K-Ras signaling. Remarkably, complete loss of Men1 created a synthetic lethal interaction with Mek1/2 inhibition. Our study suggests that inhibitors of the Raf/MEK/ERK pathway offer a rational therapy for tumors with germline or somatic MEN1 mutations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A185. Citation Format: Chester Chamberlain, Michael German. Menin functions as a gatekeeper of the proliferative MAPK arm of K-Ras signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A185.