Abstract GMM-019: MEK INHIBITOR TRAMETINIB IN HIGH GRADE OVARIAN CANCER PROLIFERATION
Authors: Mikhail Chesnokov, Anmbreen Jamroze, Wootae Ha, Ilana Chefetz
Journal: Clinical Cancer Research (2019)

Abstract A major challenge in ovarian cancer therapy is very high recurrence that is currently attributed to the presence of cancer stem-like cells (CSCs). CSCs are characterized by pronounced chemoresistance and high clonogenic ability that allow them to survive treatment and trigger relapse. The search for new treatment approaches capable of eradicating CSCs is crucial to prevent recurrent disease. Despite lack of BRAF or KRAS mutations in high grade serous ovarian cancer, MEK1/2-ERK1/2 pathway is activated in ovarian cancer cell lines and primary tumors. The aim of present work was to evaluate MEK inhibitor trametinib on cell proliferation and tumorigenesis. Trametinib is approved by FDA for melanoma and other solid tumors with specific BRAF mutations, thus can be used in a timely manner in clinic if found effective. We used cisplatin-resistant OVCAR8 and PEO4 cell lines displaying very high fraction of CD133-positive cells exhibiting CSC-like properties as main experimental model. Treatment of cells with trametinib caused very efficient inhibition of MEK-ERK pathway activity (up to 100% inhibition of ERK1/2 phosphorylation). Inhibition of pathway activity was confirmed by MEK-ERK-associated genes downregulation as assessed by RT-qPCR. PHLDA1, SPRY2 and DUSP4 genes were identified as early MEK responders whereas SPRY4, ETV4 and ETV5 were responsive to prolonged MEK inhibition. Trametinib treatment resulted in significant reduction of cell growth rate and number of viable cells (5-fold reduction with 100nM trametinib, p&amp;lt;0.05) in both cell lines. Cell cycle assay demonstrated cell cycle arrest in G1/0 -phase indicating that MEK-ERK activation is required for transition from G1 to S-phase. To further elaborate associations between MEK pathway activity and cell proliferation, we studied cells enriched in different stages of S- and G2-phase. MEK pathway activity was subject to prominent activation during S-phase reflected by significant increase in phosphorylation levels of ERK1/2, its direct targets FRA1 and p90RSK and subsequent upregulation of reporter genes PHLDA1, SPRY2 and DUSP4. Our data indicate that trametinib treatment may induce efficient inhibition of ovarian cancer cell proliferation and therefore may have positive impact upon duration of remission for ovarian cancer patients. While trametinib alone is not capable of eradicating ovarian CSCs, its combinations with other drugs may provide a promising tool for ovarian cancer treatment, especially for tumors with high level of MEK-ERK pathway activity. One of such drugs to use in conjunction with trametinib can be Aldehyde Dehydrogenase (ALDH) inhibitor 673A that was previously characterized in our research as a compound capable of inducing cell programed necroptosis in ovarian CSCs. Citation Format: Mikhail Chesnokov, Anmbreen Jamroze, Wootae Ha, Ilana Chefetz. MEK INHIBITOR TRAMETINIB IN HIGH GRADE OVARIAN CANCER PROLIFERATION [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-019.