Abstract 2000: Cancer metastasis driven by the novel MEK1 substrate MACC1 is restricted by clinically applicable MEK1 inhibitors

Abstract

Abstract Cancer metastasis is responsible for >90% of cancer deaths and remains a major treatment challenge. In search of new drivers of metastasis we identified the novel, previously undescribed gene Metastasis-Associated in Colon Cancer 1 (MACC1) in human colorectal cancer (CRC). MACC1 induces fundamental processes like proliferation, migration, invasiveness and metastasis in xenografted and transgenic mice. MACC1 has been established by us and many other groups as key player, prognostic and predictive biomarker for tumor progression and metastasis in >20 solid cancer types. Proof-of-concept for MACC1 as a therapeutic target to restrict cancer progression and metastasis was provided by transcriptional and post-transcriptional downregulation of MACC1 for several solid cancers, including CRC. Specific inhibitors targeting MACC1 post-translational protein modifications to restrict tumor growth and metastasis are not identified so far. Here we report the identification of MACC1 as a newly identified substrate of the kinase MEK1 (MAP2K1). MEK1 directly phosphorylates MACC1 leading to accelerated and increased ERK1 activation. Mutating three potential hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1 dependent target gene expression like MET, cell proliferation and motility in cell culture and importantly, metastasis in mouse xenograft models. Targeting MEK1 by RNAi or by clinically applicable MEK1 inhibitors like AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation. Our findings demonstrate that MAP kinase signaling is not linearly leading only to ERK activation, but branches at the level of MEK1. In summary, MACC1 tyrosine phosphorylation is decisive for tumor growth and metastasis. The fundamental finding of MACC1 being a newly identified MEK1 substrate opens new therapeutic options with potential for clinical translation. Targeting MACC1 tyrosine phosphorylation using MEK1 inhibitors thereby intervening in MACC1-induced metastasis aims at the ultimate goal of personalized therapies for inhibition of cancer progression and metastasis, resulting in improved patient survival. Since MACC1 is confirmed as decisive driver for tumor growth and metastasis in a variety of solid cancers, the findings made here for CRC might be translated to further solid tumor types. The usefulness of MACC1 as therapeutic target towards MEK1 inhibitor treatment requires confirmation in clinical trials. Citation Format: Dennis Kobelt, Daniel Perez-Hernandez, Claudia Fleuter, Mathias Dahlmann, Fabian Zincke, Janice Smith, Rebekka Migotti, Susen Burock, Wolfgang Walther, Gunnar Dittmar, Ulrike S. Stein. Cancer metastasis driven by the novel MEK1 substrate MACC1 is restricted by clinically applicable MEK1 inhibitors [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 2000.