The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis

Dennis Kobelt,Fabian Zincke,Wolfgang Walther,Claudia Fleuter,Susen Burock,Oliver Popp,Gunnar Dittmar,Mathias Dahlmann,Rebekka Migotti,Janice Smith,Philipp Mertins,Daniel Perez-Hernandez,Ulrike Stein

doi:10.1038/s41388-021-01917-z

Abstract

Cancer metastasis causes >90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate. MEK1 directly phosphorylates MACC1, leading to accelerated and increased ERK1 activation. Mutating in silico predicted hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1-induced migration, invasion, and MET expression, a transcriptional MACC1 target. Targeting MEK1 by RNAi or clinically applicable MEK1 inhibitors AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation in mice. Although MEK1 levels, contrary to MACC1, are not of prognostic relevance for CRC patients, MEK1 expression was found indispensable for MACC1-induced metastasis. This study identifies MACC1 as new MEK1 substrate for tyrosine phosphorylation decisively impacting cell motility, tumor growth, and metastasis. Thus, MAP kinase signaling is not linear leading to ERK activation, but branches at the level of MEK1. This fundamental finding opens new therapeutic options for targeting the MEK1/MACC1 axis as novel vulnerability in patients at high risk for metastasis. This might be extended from CRC to further solid tumor entities.

Highlights

Colorectal cancer (CRC) metastasis is directly linked to patient survival and accounts for 90% of patient deaths
MEK1 inhibitors restrict Metastasis Associated in Colon Cancer 1 (MACC1)-induced cell motility in vitro In our seminal discovery of MACC1, we identified this gene as prognostic biomarker for CRC
MEK1 inhibitors UO126 and PD98059 restricted MACC1-induced cell scattering, indicating that MAPK signaling is important for MACC1 function [4]

Summary

Introduction

Colorectal cancer (CRC) metastasis is directly linked to patient survival and accounts for 90% of patient deaths. It critically limits successful therapy, representing the most frequent cause of treatment failure [1,2,3]. Biomarkers for metastasis prediction, for identification of high-risk patients at early stages, and as targets for therapeutic interventions are of upmost importance. We previously identified the gene Metastasis Associated in Colon Cancer 1 (MACC1) in human CRC [4]. MACC1 transcripts in CRC patient’s tumor tissue and blood predict metastasis formation and patient survival, thereby allowing the early identification of high-risk patients [4, 6, 8–14,]. MACC1 has been confirmed as prognostic and predictive biomarker in a variety of solid cancers like CRC, gastric, esophageal, pancreatic, hepatocellular/biliary, lung, ovarian, breast, renal, bladder, nasopharyngeal cancer, glioblastoma, and osteosarcoma [16–

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