Exploiting MEK Inhibitor-Mediated Activation of ERα 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 ERα expression and hormonal resistance in numerous malignancies. Herein, we demonstrate that MEKi induces a feedback response that results in ERα overexpression, phosphorylation and transcriptional activation of ER-regulated genes. Mechanistically, MEKi-mediated ERα 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 ERα-positive tumors to hormonal therapy, and propose that this strategy may have broader clinical utility in ERα-positive ovarian carcinoma.

MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer

“…Anti-estrogen responses were restored by MEK inhibition with re-expression of ERα in a subset of ER negative breast cancer cells (35). Similarly, MEK inhibition with PD0325901 increased ER, sensitizing the SKOV3 OVCA line to ER blockade (50). …”

Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line

“…Based on profiling done against a panel of 80 kinases, PD0325901 has been shown to have high specificity towards MEK1/2 [7]. PD0325901 and KU0063794 have been tested widely in preclinical in vitro and in vivo models of human cancers such as breast, ovarian, non-small cell lung, and renal-cell carcinoma and glioblastoma [7,[20][21][22][23].…”

IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors

“…At doses equivalent to or below those required to limit proliferation of A2780 ovarian cancer cells – known to be sensitive to PI3K and MEK inhibitors (23, 24) – a variety of inhibitor classes prevented ConA-driven T cell expansion (Figure 1A). Small molecules targeting PI3K, mTOR, MAPK, and CDK signaling, as well as transcriptional regulators (HDACs) and survival molecules (Bcl-2) were deleterious for T cell expansion.…”