Abstract B13: COP1-ETS axis regulates ERK transcriptional output and modulates sensitivity to MAPK inhibitors

Abstract

Abstract Aberrant activation of the mitogen activate kinase (MAPK) pathway is highly prevalent in cancer and therapies targeting the pathway are approved or under active investigation in multiple malignancies. MAPK signaling leads to activation of a transcriptional program that includes general growth promoting genes, negative feedback regulators of the MAPK pathway, and lineage-specific genes. While the mechanisms of upstream signal transduction that leads to MAPK activation have been studied in detail, how MAPK activation is dynamically coupled with downstream nuclear transcriptional response is not fully understood. In gastrointestinal stomal tumor (GIST) and melanoma, two malignancies with aberrant MAPK activation, we find that Pea3 family ETS transcription factors ETV1, ETV4, and ETV5 are critical nuclear effectors of MAPK signaling. We find that the primary mechanism linking MAPK and Pea3 activity is through protein stability via the COP1 E3 ligase. The loss of COP1 leads to decoupling between upstream MAPK signaling and downstream transcription with constitutively stabilized Pea3 protein levels, constitutively high MAPK transcriptome, yet decreased upstream signaling due to Pea3-mediated transcription of negative feedback regulators. This leads to decreased therapeutic sensitivity to MAPK pathway inhibition in vitro and in vivo. These observations indicate that MAPK signaling-dependent regulation of Pea3 ETS protein stability is a crucial pathway that couples downstream transcriptional response to MAPK signaling and can shape the therapeutic sensitivity to MAPK pathway inhibition in cancer. Citation Format: Yuanyuan Xie, Zhen Cao, Wai Pung Wong, Youxin Guan, Jenny Zhang, Edward Walczak, Devan Murphy, Leili Ran, Inna Sirota, Shangqian Wang, Shipra Shukla, Dong Gao, John Wongvipat, Simon Knott, Kenneth Chang, Cristina Antonescu, Gregory Hannon, Ping Chi, Yu Chen. COP1-ETS axis regulates ERK transcriptional output and modulates sensitivity to MAPK inhibitors [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B13.