Abstract 3242: The role of SERPINE1 in trametinib resistance in low-grade ovarian serous cancer cell line

Abstract

Abstract Ovarian cancer is the deadliest gynecological cancer. The dismal 5-year survival rate is partly due to late-stage diagnosis. MEK inhibition therapy has been approved by FDA as treatment option for several cancer types. Recently, trametinib has achieved significantly better objective response rate than traditional standard of care therapies in patients with recurrent low-grade ovarian serous cancer (LGOSC). However, adaptive resistance to MEK inhibitors is common and the mechanism is still unclear. To further investigate the mechanism of adaptive resistance, we have established several adaptive trametinib resistant ovarian cancer cell lines. Our result showed that SERPINE1 was significantly induced in a LGOSC cell line, HOC-7, after acquiring trametinib resistance. To determine the role of SERPINE1 in trametinib resistance in LGOSC, overexpression and down-regulation of SERPINE1 in HOC-7 were achieved by transfection with a cDNA clone expressing SERPINE1 and siRNA silencing respectively. The association of SERPINE1 with trametinib resistance was also investigated in a LGOSC mouse model. For in vitro studies, HOC-7 overexpressing SERPINE1 had a 5-fold increase in IC50 to trametinib in comparison to the parental control cell line HOC-7. Furthermore, pERK expression was also up-regulated in HOC-7 overexpressing SERPINE1. By knocking down the expression of SERIPINE1 in trametinib adaptive resistant HOC-7 cells transfected with SERPINE1 siRNA, we found that the cell proliferation was partly reduced in comparison to cells transfected with control siRNA. More importantly, the trametinib adaptive resistant cells became more sensitive to trametinib. For in vivo studies with the LGOSC mouse model, we found that SERPINE1 expression increased after trametinib treatment in LGOSC tumor tissue. Interestingly, the expression of SERPINE1 protein was found to be correlated to ERK phosphorylation in tumor tissues. Furthermore, the measurement of plasma SERPINE1 in LGOSC mouse model and cancer patient revealed that SERPINE1 could be a predictive marker in cancer diagnosis and prognosis. The above observations were further supported by CCLE and TCGA data that SERPINE1 gene expression level correlated with trametinib sensitivity and patient survival. In conclusion, SERPINE1 could facilitate trametinib resistance by ERK phosphorylation, and this protein has the potential to be a therapeutic target, diagnostic and prognostic biomarker for LGOSC. Further analysis by RNA-seq and immunohistochemical staining of trametinib-treated mouse tumor samples will be performed to understand the mechanism of MEK inhibitor adaptive resistance. Citation Format: Chun Wai Ng, Yvonne TM Tsang, David M. Gershenson, Kwong-Kwok Wong. The role of SERPINE1 in trametinib resistance in low-grade ovarian serous cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3242.