Low-grade ovarian serous carcinomas (OSC) account for more than 70% epithelial ovarian cancers in young women. The exact biological pathways that underlie this disease are elusive. Moreover, chemotherapy and hormonal therapy are relatively ineffective and have generally failed to reduce the high morbidity and mortality associated with this disease. Because the Ras/Raf/MEK/ERK pathway is frequently activated in low-grade OSC, targeting this pathway has been examined as a potential avenue for treatment. Results from a phase II Gynecologic Oncology Group (GOG) trial for patients with recurrent low-grade OSC indicated a majority of the patients had developed resistance to Selumetinib (a MEK inhibitor). There were one complete responder, seven partial responders and 34 patients with stable disease out of the 52 patients treated with the MEK inhibitor. In order to understand the MEK inhibitor adaptive response, we have generated two MEK inhibitor (MEKi) adaptive resistant low-grade OSC cell lines. Using functional proteomic analysis by reverse phase protein array (RPPA), we identified several signaling pathways affected by MEKi (trametinib). Our data indicated pAKT was the most up-regulated protein by MEKi. In addition, other proteins in the mTOR, NF-kB, RTK and immune suppressive pathways were up-regulated. We further validated the result by western blot analysis, phospho-ERK, CHK1, MSH2, pRB and DUSP6 were down-regulated, while pAKT, B7-H4, BIM, and p27 were significantly up-regulated. More interestingly, SERPINE1 was the only highly expressed protein in both MEKi adaptive resistance low-grade OSC cell lines, and its expression was not affected by MEKi treatment. Knocking down the expression of SERPINE1 by siRNA targeting SERPINE1 in the MEKi-resistant low-grade OSC cell line was able to attenuate its resistance to trametinib. In summary, we have deciphered several adaptive responses of low-grade ovarian cancer cell lines to MEK inhibitor and the up-regulation of the SERPINE1 pathway is partly responsible for the development of adaptive resistance.
Citation Format: Kwong-Kwok Wong, Yvonne T Tsang, Michelle Chen, Eucharist H Kun, David M Gershenson. Adaptive responses of low-grade ovarian cancer cell lines to MEK inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C089. doi:10.1158/1535-7163.TARG-19-C089