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Am J Cancer Res. 2016 Oct 1;6(10):2235-2251. eCollection 2016.

Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines.

Author information

1
Department of Obstetrics & Gynaecology, University of British Columbia Vancouver, British Columbia, Canada.
2
Translational Ovarian Cancer Research Program, London Regional Cancer ProgramLondon, Ontario, Canada; Department of Biochemistry, University of Western OntarioLondon, Ontario, Canada; Department of Obstetrics & Gynecology, University of Western OntarioLondon, Ontario, Canada; Department of Oncology, University of Western OntarioLondon, Ontario, Canada.
3
Department of Reproductive and Developmental Sciences, University of British Columbia Vancouver, British Columbia, Canada.
4
Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia Vancouver, British Columbia, Canada.
5
Beaumont Hospital and Royal College of Surgeons of Ireland Dublin, Ireland.
6
Department of Obstetrics & Gynaecology, University of British ColumbiaVancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British ColumbiaVancouver, British Columbia, Canada.
7
Translational Ovarian Cancer Research Program, London Regional Cancer ProgramLondon, Ontario, Canada; Department of Obstetrics & Gynecology, University of Western OntarioLondon, Ontario, Canada; Department of Oncology, University of Western OntarioLondon, Ontario, Canada; Department of Anatomy and Cell Biology, University of Western OntarioLondon, Ontario, Canada.
8
Department of Pathology and Laboratory Medicine, University of British Columbia Vancouver, British Columbia, Canada.
9
Department of Medical Oncology, BC Cancer Agency Vancouver, British Columbia, Canada.
10
Department of Obstetrics & Gynaecology, University of British ColumbiaVancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British ColumbiaVancouver, British Columbia, Canada; Department of Molecular Oncology, BC Cancer AgencyVancouver, British Columbia, Canada.
11
Department of Obstetrics & Gynaecology, University of British ColumbiaVancouver, British Columbia, Canada; Department of Surgical Oncology, BC Cancer AgencyVancouver, British Columbia, Canada.

Abstract

Advanced or recurrent low-grade serous ovarian cancers (LGSC) are resistant to conventional systemic treatments. LGSC carry mutations in RAS or RAF, leading to several clinical trials evaluating MEK inhibitors (MEKi). As LGSC cell lines and xenografts have been difficult to establish, little is known about the efficacy and on-target activity of MEKi treatment in this disease. We compared four different MEKi (trametinib, selumetinib, binimetinib and refametinib) in novel LGSC patient-derived cell lines. Molecular characterization of these cells included copy-number variation and hotspot mutational analysis. Proliferation, apoptosis and cell viability assays were used to study drug efficacy. MEKi on-target efficacy was measured using western blotting and isoelectric point focusing for ERK1/2 phosphorylation. Ten LGSC cell lines were derived from 7 patients with advanced/recurrent disease. Copy number variation showed significant heterogeneity among cell lines, however all samples showed deletions in chromosome 9p21.3, and frequent copy number gains in chromosomes 12 and 20. Mutations in KRAS/NRAS were identified in 4 patients (57%) and RAS mutation status was not associated with higher baseline levels of ERK phosphorylation. Different degrees of MEKi sensitivity were observed in the LGSC cell lines. Two cell lines, both with KRAS mutations, were highly sensitive to MEKi. Drug anti-proliferative efficacy correlated with the degree of inhibition of ERK phosphorylation, with trametinib being the most potent agent. Differences in MEKi efficacy were observed in LGSC cell lines. Trametinib showed the greatest anti-proliferative effects. This study serves as a basis for much needed future research on MEKi drug efficacy in LGSC.

KEYWORDS:

ERK1/2 phosphorylation; Low-grade serous ovarian cancer; MAPK signalling; MEK inhibitors; cell line models; copy-number alterations; gene mutations

PMID:
27822414
PMCID:
PMC5088288

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