Exploiting MEK inhibitor-mediated activation of ER? for therapeutic intervention in ER-positive ovarian carcinoma.

ABSTRACT: While the clinical benefit of MEK inhibitor (MEKi)-based therapy is well established in Raf mutant malignancies, its utility as a suppressor of hyperactive MAPK signaling in the absence of mutated Raf or Ras, is an area of ongoing research. MAPK activation is associated with loss of ER? expression and hormonal resistance in numerous malignancies. Herein, we demonstrate that MEKi induces a feedback response that results in ER? overexpression, phosphorylation and transcriptional activation of ER-regulated genes. Mechanistically, MEKi-mediated ER? overexpression is largely independent of erbB2 and AKT feedback activation, but is ERK-dependent. We subsequently exploit this phenomenon therapeutically by combining the ER-antagonist, fulvestrant with MEKi. This results in synergistic suppression of tumor growth, in vitro and potentiation of single agent activity in vivo in nude mice bearing xenografts. Thus, we demonstrate that exploiting adaptive feedback after MEKi can be used to sensitize ER?-positive tumors to hormonal therapy, and propose that this strategy may have broader clinical utility in ER?-positive ovarian carcinoma.

SUBMITTER: Hou JY 

PROVIDER: S-EPMC3563537 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature