Abstract 7209: Overcoming platinum resistance of high-grade serous ovarian cancer targeting the activated JAK/STAT pathways via extracellular vesicles
Authors: Suzuki Kazuhiro , Yokoi Akira , Yoshida Kousuke , Yamamoto Yusuke , Kajiyama Hiroaki 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. While HGSOC usually responds to initial treatment, most cases eventually relapse and develop platinum-resistant ovarian cancer (PROC). The molecular definition of PROC is still unclear, and overcoming PROC has been the biggest challenges. Extracellular vesicles (EVs) have an essential role in cell-to-cell communication within both the primary and distant microenvironments. In this study. we aimed to identify molecular mechanisms of PROC via EVs to suggest novel therapeutic strategies. Platinum responses were categorized by primary treatment-free interval of platinum less than 6 months as PROC, and more than 36 months as platinum good response. Ascites and tumor tissues have been collected prior to initial chemotherapy in patients with HGSOC for analysis according to platinum response. mRNA sequencing in tumor tissues identified significantly upregulated JAK/STAT pathways in PROC. The JAK/STAT family was highly expressed in PROC than the good response group, and also increased than adjusted normal ovaries and fallopian tubes. In addition, PROC cell lines and PROC patient-derived xenograft model tumor tissues showed high JAK expression. Small RNA sequencing for HGSOC tissues and ascites-EVs revealed that miR-135a-5p and miR-221-5p were highly expressed in both PROC tissues and ascites, and the expression of the two miRNAs had a positive correlation between tissues and ascites. Overexpression of the two miRNAs in HGSOC cell lines resulted in higher JAK family expression and resistance to cisplatin. JAK inhibitors (JAKi) had equivalent efficacy for platinum-sensitive/resistant HGSOC cell lines and JAKi highly suppress tumor growth in the PROC mouse model. In addition, suppression of JAK family expression in PROC cell lines significantly increased sensitivity to cisplatin. JAKi also had a synergistic effect with cisplatin for PROC cell lines. IPA analyses in mRNA sequencing in tumor tissues, TGF-β was highly expressed in upstream regulators in PROC, and TGF-β stimulation resulted in the upregulation of the two miRNAs in mesothelial cells, but not in HGSOC cell lines and fibroblasts. In summary, we here demonstrate novel molecular mechanisms of PROC via EVs and provided the rationale for JAK-targeted therapy for PROC. EV-miRNAs can regulate the PROC activated JAK/STAT pathway and can be diagnostic and therapeutic biomarkers for PROC definition or JAKi indications, suggesting that patient stratification in precision medicine for initial treatment of HGSOC.
Citation Format: Kazuhiro Suzuki, Akira Yokoi, Kousuke Yoshida, Yusuke Yamamoto, Hiroaki Kajiyama. Overcoming platinum resistance of high-grade serous ovarian cancer targeting the activated JAK/STAT pathways via extracellular vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7209.