Abstract 2432: Somatic mutations in the STAT3 activation pathway are associated with improved survival in gynecologic malignancies and provide a molecular rationale for therapeutic targeting

Abstract

Abstract Background: Signal transducer and activator of transcription 3 (STAT3) activation promotes tumor cell survival, immune evasion, metastasis, and drug resistance in PARP inhibitors and platinum-based chemotherapy. Objective: Based on our in-vitro findings of the tumoricidal potential of STAT3 inhibition in BRCAwild-type and PARP inhibitor-resistant tumor cells, we sought to evaluate whether ovarian and uterine cancer patients with somatic mutations in the STAT3 activation pathway had improved overall survival (OS) compared to those with intact STAT3 activation pathway-related genes. Method: We induced Olaparib resistance in BRCAwild-type ovarian cancer cell lines (OVCAR8 and A2780) and treated both parental and PARP inhibitor-resistant cell lines with various STAT3 inhibitors. We then attempted to establish clinical correlations of our in-vitro studies and queried the Cancer Genome Atlas (TCGA) Pan-Cancer Atlas for uterine and ovarian cancers. OS in patients with somatic mutations in the STAT3 gene and/or associated STAT3 activation genes (IL6ST, GNAS, JAK1, JAK2) was compared to OS in patients with intact STAT3 pathway-related genes. Kaplan-Meier survival curves were compared using the log-rank test. Results: In-vitro, STAT3 inhibition demonstrated potent, tumoricidal propensity in all cell lines (EC50: 0.34uM-0.46uM) including A2780parental, A2780parpi-resistant, OVCAR8parental, and OVCAR8parpi-resistant. Clinically, 1,154 total patients were identified in TCGA, including 571 high-grade serous ovarian carcinoma, 397 uterine endometrioid adenocarcinomas, 109 uterine serous carcinoma/uterine papillary serous carcinomas, 56 uterine carcinosarcomas/uterine malignant mixed Mullerian tumors, and 21 uterine mixed endometrial carcinomas. When pooling all uterine and ovarian cancer patients, median survival (MS) was 52 months (0-185) in patients with intact STAT3 (n=1,007) compared to not reached (NR, 0-225) in the STAT3 mutated group (n=147) with a Hazard Ratio (HR) of 0.25 and Confidence Interval (CI) 0.20-0.32 (p<0.001). In ovarian cancer patients, MS was 45 months (0-180) in patients with intact STAT3 (n=551) compared to 95 months (0-145) in the STAT3 mutated group (n=20) with a HR of 0.48 and CI 0.29-0.80 (p=0.038). In uterine cancer patients, MS was 112 months (0-185) in patients with intact STAT3 (n=456) compared to NR (0-225) in the STAT3 mutated group (n=127) with a HR of 0.40 and CI 0.25-0.64 (p=0.003). Conclusion: Pharmacologic and genetic (siRNA) inhibition of the STAT3 activation pathway killed PARP inhibitor-resistant ovarian cancer cells in-vitro. Clinically, somatic mutations in the STAT3 activation pathway were associated with improved OS in both ovarian and uterine cancer. These findings provide a rationale for the therapeutic targeting of this pathway in gynecologic malignancies. Citation Format: Adrian Kohut, Antons Martincuks, Thanh Dellinger, Hua Yu, Lorna Rodriguez-Rodriguez. Somatic mutations in the STAT3 activation pathway are associated with improved survival in gynecologic malignancies and provide a molecular rationale for therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2432.