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Assessment of Ovarian Cancer Spheroid Attachment and Invasion of Mesothelial Cells in Real Time
Published on: May 20, 2014
Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines
Marta Llauradó Fernández1, Gabriel E DiMattia2, Amy Dawson3
1Department of Obstetrics & Gynaecology, University of British Columbia Vancouver, 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.
Insights
Low-grade serous ovarian cancer (LGSC) shows resistance to standard treatments. Novel cell lines reveal MEK inhibitors (MEKi) efficacy varies, with trametinib showing the most promise against LGSC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Advanced or recurrent low-grade serous ovarian cancers (LGSC) are challenging to treat with conventional therapies.
- LGSC harbors RAS/RAF mutations, prompting investigation into MEK inhibitors (MEKi) despite limited preclinical models.
- Establishing LGSC cell lines is difficult, hindering research into MEKi efficacy and on-target activity.
Purpose of the Study:
- To evaluate the efficacy and on-target activity of four MEK inhibitors (MEKi) in novel low-grade serous ovarian cancer (LGSC) patient-derived cell lines.
- To characterize the molecular landscape of these LGSC cell lines, including copy-number variation and hotspot mutations.
- To assess the correlation between MEKi efficacy and inhibition of ERK1/2 phosphorylation.
Main Methods:
- Development and molecular characterization (copy-number variation, mutational analysis) of ten LGSC cell lines from seven patients.
- Assessment of MEKi (trametinib, selumetinib, binimetinib, refametinib) efficacy using proliferation, apoptosis, and viability assays.
- Measurement of MEKi on-target activity via western blotting and isoelectric point focusing for ERK1/2 phosphorylation.
Main Results:
- LGSC cell lines exhibited significant copy-number variation, with common deletions at 9p21.3 and gains at chromosomes 12 and 20.
- KRAS/NRAS mutations were found in 57% of patients, but not associated with baseline ERK phosphorylation.
- Variable MEKi sensitivity was observed; two KRAS-mutated cell lines were highly sensitive, and trametinib demonstrated the most potent anti-proliferative effect, correlating with ERK inhibition.
Conclusions:
- Novel LGSC cell lines provide a valuable platform for studying MEKi efficacy.
- MEKi sensitivity varies in LGSC, with trametinib showing significant potential.
- Further research into MEKi drug efficacy in LGSC is warranted, particularly for patients with KRAS mutations.
