Abstract 4862: Investigation of the JAK/STAT signaling pathway in chemotherapy and PARP inhibitor resistant ovarian cancer

Abstract Ovarian cancer is the 7th most common cancer in women and the most fatal of all female reproductive cancers, with 5-year overall survival of 10-30%. Despite initial responses to first line platinum- and paclitaxel-based chemotherapies, >70% of ovarian cancers recur with increasingly resistant disease; and nearly all of these women die of their disease. Recently, the use of targeted therapies such as bevacizumab and PARP inhibitors have been shown to improve progression-free survival in a subset of patients. However, these agents have thus far failed to improve overall survival in patients without specific genetic signatures, highlighting the continued need for alternative therapies. Through an unbiased drug screen, we have identified lestaurtinib as a potent inhibitor of many sensitive and resistant ovarian cancer cell lines and patient derived organoid models. Lestaurtinib is a known tyrosine kinase inhibitor originally developed to block FLT3, a protein that is not expressed in any of the ovarian cancer cell lines tested. To elucidate the mechanisms by which lestaurtinib inhibits ovarian cancer cells, we have examined its impact on the phospho-proteome in parallel with RNAseq. Results of these studied have identified inhibition of the JAK/STAT signaling pathway as a top hit. Assessment of STAT1 and STAT3 has revealed that these transcription factors are constitutively activated in chemotherapy- and PARP inhibitor-resistant cell lines as reflected by high levels of Tyr701/705 and Ser727 phosphorylation, suggesting that induction of this pathway may drive resistance. Surprisingly, profound differences in the ability of various JAK/STAT inhibitors to block these specific phosphorylation events is observed, which correlates with their potency. Further, STAT1 and STAT3 ChIPseq experiments following cytokine-mediated activation of this pathway reveal that these transcription factors bind to genomic regions encoding genes involved in oncogenic and drug resistance pathways. Genetic knockdown of STAT1 and STAT3 via siRNA, or knockout via CRISPR/Cas9, results in significant growth inhibition of sensitive and resistant models of ovarian cancer, confirming their importance in maintaining cell viability. Finally, combining lestuartinib with standard-of-care cisplatin or olaparib (a PARP inhibitor) is shown to be synergistic, indicating that pharmacological inhibition of JAK/STAT signaling has the potential to counteract drug resistance. Ongoing studies are aimed at further understanding the role of JAK/STAT signaling in ovarian cancer, elucidating the mechanistic processes by which STAT1/3 mediate progression of this disease, and identifying the most effective pharmacological strategies to study in possible future clinical trials. Citation Format: Esther Rodman, Michael Emch, Elizabeth Bruinsma, Xiaonan Hou, Scott Kaufmann, Saravut J. Weroha, John Hawse. Investigation of the JAK/STAT signaling pathway in chemotherapy and PARP inhibitor resistant ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4862.