Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines.
Advanced or recurrent low-grade serous ovarian cancers (LGSC) are resistant to conventional systemic treatments. LGSC carry mutations inRASorRAF, 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 inKRAS/NRASwere 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 withKRASmutations, 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.
Department of Obstetrics & Gynaecology, University of British Columbia Vancouver, British Columbia, Canada.
Marta Llauradó
ML
Fernández
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.
Gabriel E
GE
DiMattia
Department of Reproductive and Developmental Sciences, University of British Columbia Vancouver, British Columbia, Canada.
Amy
A
Dawson
Department of Obstetrics & Gynaecology, University of British Columbia Vancouver, British Columbia, Canada.
Sylvia
S
Bamford
Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia Vancouver, British Columbia, Canada.
Shawn
S
Anderson
Beaumont Hospital and Royal College of Surgeons of Ireland Dublin, Ireland.
Bryan T
BT
Hennessy
Department of Obstetrics & Gynaecology, University of British ColumbiaVancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British ColumbiaVancouver, British Columbia, Canada.
Michael S
MS
Anglesio
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.
Trevor G
TG
Shepherd
Department of Pathology and Laboratory Medicine, University of British Columbia Vancouver, British Columbia, Canada.
Clara
C
Salamanca
Department of Obstetrics & Gynaecology, University of British Columbia Vancouver, British Columbia, Canada.
Josh
J
Hoenisch
Department of Medical Oncology, BC Cancer Agency Vancouver, British Columbia, Canada.
Anna
A
Tinker
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.
David G
DG
Huntsman
Department of Obstetrics & Gynaecology, University of British ColumbiaVancouver, British Columbia, Canada; Department of Surgical Oncology, BC Cancer AgencyVancouver, British Columbia, Canada.
Mark S
MS
Carey
ERK1/2 phosphorylation; Low-grade serous ovarian cancer; MAPK signalling; MEK inhibitors; cell line models; copy-number alterations; gene mutations