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UBC Theses and Dissertations

Targeted therapy in low-grade serous ovarian carcinoma : characterization of MEK inhibitor response in novel patient-derived cell lines Dawson, Amy


Low-grade serous ovarian carcinoma, or LGSOC, predominantly occurs in pre- menopausal women at lower frequency than the more common high-grade serous ovarian carcinoma. It tends to harbour few, but distinct, mutations, with a significant proportion of RAS oncogene mutations. Aberrations of the RAS-MAPK signaling pathway in LGSOC have led to the initiation of several clinical trials of MEK inhibitors in this disease. Due to the relative rarity of LGSOC, few representative model systems are available. Accordingly, there has been a lack of preclinical investigational drug testing in this disease. In this study, 11 histotype-specific cell lines have been derived and molecularly characterized in order to further elucidate the molecular biology of the disease, and serve as an important platform to test novel therapeutics in LGSOC. The most common missense mutations by HotSpot mutational profiling analysis were oncogenic KRAS/NRAS mutations, and varying levels of copy number aberration were seen. All cell lines were uniquely identifiable by short-tandem repeat analysis, with the exception of two patient-paired cell lines. The phenotypic and molecular responses to the 4 MEK inhibitors (MEKi) trametinib, selumetinib, refametinib, and binimetinib have been characterized in selected LGSOC cell lines through IC50 analysis, proliferation, viability, and apoptosis assays, and on-target drug effects by Western blot. Of the 4 MEKi, trametinib exhibited the best anti-proliferative effects and inhibition of MEK kinase activity. Biological and on-target data from two of the cell lines reveals an exquisite sensitivity to MEK inhibition. Reverse-phase protein array and quantitative mass spectrometry global proteomic analysis on control and MEKi-treated LGSOC cell lines was performed in order to examine basal proteomic differences between MEKi-sensitive and resistant LGSOC cell lines and gather data for examining proteomic changes upon MEKi treatment. Three significantly differentially expressed protein candidates (PKCα, EGFR, and Smac/DIABLO were identified between sensitive and resistant cell lines under control and MEKi treatment conditions by both proteomic platforms. Results from therapeutic testing in these pathologically reviewed, histotype- specific LGSOC models allow for a comparison of the overall efficacies of the 4 MEKi, characterization of drug sensitivity in novel cell lines, and identification of potential functional markers of MEKi response.

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