NRAS upregulation or gain-of-function mutation confers susceptibility to the MEK inhibitor trametinib in ovarian cancer models outside the LGSC setting

Ovarian cancer (OC) is an aggressive gynecologic cancer characterized by immense difficulty in early diagnosis and high probability of recurrence. Although many patients are responsive to platinum-based chemotherapy, recurring tumors are frequently chemoresistant, urging the exploration of alternative therapies. The RAS/RAF/MEK/ERK pathway, which may be attributed to mutations to RAS proteins, has various effects on tumor progression and chemoresistance. Therefore, the MEK inhibitor trametinib was employed to target this pathway. The present study aims to investigate the role of NRAS, which is a member of the RAS protein family, and the NRAS Q61K mutation in OC cell behavior and trametinib susceptibility outside the low-grade serous carcinoma (LGSC) setting. Three non-LGSC OC cell lines (TOV112D, OVCA433, and ES2) were transduced with retroviruses to induce wild-type NRAS or NRAS Q61K and subjected to functional assays with or without trametinib and/or cisplatin to characterize behavior pre- and post-treatment. NRAS promoted the proliferation, migratory and invasive capacities of OC cells. Moreover, NRAS Q61K OC cells exhibited higher migratory and invasive capacities and heightened susceptibility to MEK inhibition, which also enhanced cisplatin cytotoxicity. NRAS Q61K mutation confers susceptibility to the MEK inhibitor trametinib in selected engineered OC models outside the LGSC setting.