Abstract 3060: YAP1 induces STAT3 phosphorylation & combined blockade enhances chemotherapeutic efficacy

Recent studies have identified transcriptions factors YAP1 and STAT3, as therapeutic targets in cancer, but efforts targeting either YAP1 or STAT3 pathway have met with limited success. Our study is focused on understanding the cross-talk between YAP1 and STAT3 signaling, impact of this cross-talk on lung tumorigenesis, drug resistance and blocking this pathway as a potential therapeutic strategy in lung adenocarcinoma (LUAD). Mechanistically, we demonstrate that YAP1 promotes the phosphorylation of STAT3 through IL-6 upregulation. In clinical LUAD samples, a positive correlation between YAP1 and phosphorylated STAT3 protein as well as an association between YAP1 and IL-6 mRNA was observed. Pre-clinically, genetic and pharmacologic dual inhibitions of YAP1 and STAT3 showed decreased cell growth and increased sensitivity to chemotherapy through the attenuation of cancer-stemness like features. Although verteporfin and S3I-201 were employed as YAP1 and STAT3 inhibitors respectively, verteporfin was found to suppress not only YAP1 but also STAT3, and their combination induced synergistic cytotoxic effects. Furthermore, addition of verteporfin and S3I-201 to standard-of-care chemotherapy regimen significantly inhibited tumor growth in patient-derived xenograft mouse models and attenuated in vivo expansion of malignant stemness. These findings provide the conceptual framework for combined targeting of YAP1 and STAT3 in LUAD. Citation Format: Masahiro Shibata, Akira Ooki, Yoshikuni Inokawa, Evgeny Izumchenko, Enrico Munari, Giuseppe Bogina, Edward Gabrielson, Anju Singh, Mohammad Obaidul Hoque. YAP1 induces STAT3 phosphorylation & combined blockade enhances chemotherapeutic efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3060.