Exploiting MEK Inhibitor-Mediated Activation of ERα for Therapeutic Intervention in ER-Positive Ovarian Carcinoma

June Y. Hou, Alicia Rodriguez-Gabin, Leleesha Samaweera, Rachel Hazan, Gary L. Goldberg, Susan Band Horwitz, Hayley M. McDaid

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere54103
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 4 2013

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Mitogen-Activated Protein Kinase Kinases
carcinoma
Chemical activation
Carcinoma
therapeutics
neoplasms
transcriptional activation
antagonists
phosphorylation
Feedback
Tumors
Neoplasms
Bearings (structural)
mutants
mice
Therapeutics
Phosphorylation
genes
Heterografts
Nude Mice

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Exploiting MEK Inhibitor-Mediated Activation of ERα for Therapeutic Intervention in ER-Positive Ovarian Carcinoma. / Hou, June Y.; Rodriguez-Gabin, Alicia; Samaweera, Leleesha; Hazan, Rachel; Goldberg, Gary L.; Band Horwitz, Susan; McDaid, Hayley M.

In: PLoS One, Vol. 8, No. 2, e54103, 04.02.2013.

Research output: Contribution to journalArticle

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AU - Hazan, Rachel

AU - Goldberg, Gary L.

AU - Band Horwitz, Susan

AU - McDaid, Hayley M.

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