162 MEK162 (ARRY-162), a novel MEK 1/2 inhibitor, inhibits tumor growth regardless of KRas/Raf pathway mutations

Abstract

recurrence. The main molecular alterations defining high risk tumors were identified by Ingenuity Pathways Analyses software. We further validated the experimental approach and characterized the effects of TGF-b1 and the TGF-b1 receptor kinase inhibitor SB-431542 in an in vitro invasion assay with Hec1A endometrial cell line. Results: Gene expression profiling identified a number of molecular pathways associated with high risk of recurrence in endometrial cancer, and designated a prominent role to TGF-b signaling in the acquisition of an aggressive phenotype. We showed that TGF-b1 promoted morphologic and molecular alterations consistent with an epithelial to mesenchymal transition in Hec1A cells. Moreover, TGF-b1 was able to promote Hec1A cells invasion and SB-431542 reversed these effects. We further demonstrated in a 3D inverted invasion assay that the TGF-b pathway represents a key molecular event in the initial steps of carcinoma invasion. Conclusion: Our study indicates that the acquisition of a high risk of recurrence phenotype in endometrial carcinomas strongly relies on TGF-b1. The results highlight the promising utility of TGF-b pathway inhibitors for the development of targeted therapies in endometrial cancer.