# KRAS-ERK signaling drives metastasis in colorectal cancer via phosphorylation-dependent activation of the ZBTB20-TGFBR2 axis

## TL;DR

This study identifies a new signaling pathway in KRAS-mutant colorectal cancer that drives metastasis and suggests a potential treatment strategy using a TGFBR2 degrader.

## Contribution

The study reveals a novel KRAS-ERK-ZBTB20-TGFBR2 axis in metastatic colorectal cancer and validates TGFBR2 as a therapeutic target.

## Key findings

- ZBTB20 is upregulated in metastatic KRAS-mutant CRC and promotes cancer cell migration and invasion.
- KRAS/ERK signaling phosphorylates ZBTB20, enabling its nuclear localization and pro-metastatic activity.
- Pharmacological degradation of TGFBR2 inhibits metastatic outgrowth in liver and lung models.

## Abstract

Metastatic colorectal cancer (CRC) harboring KRAS mutations presents a major therapeutic challenge due to its aggressive nature, poor prognosis, and resistance to EGFR-targeted therapies. This study aimed to identify novel drivers of metastasis specifically in KRAS-mutant CRC and to elucidate the underlying molecular mechanisms to undercover new therapeutic vulnerabilities.

We integrated data from clinical databases (TCGA, CPTAC) with experimental validation using human CRC cell lines, a tissue microarray, and two distinct in vivo metastasis models (liver and lung colonization). ZBTB20 expression and function were analyzed by IHC, Western blotting, Transwell assays, and RNA-seq integrated with ChIP-seq data. The mechanism of ZBTB20 regulation was investigated via co-immunoprecipitation, mass spectrometry, truncation analysis, site-directed mutagenesis, and luciferase reporter assays. Statistical significance was determined using Student’s t-tests, ANOVA, and survival analysis.

ZBTB20 expression was significantly upregulated with metastatic progression specifically in KRAS-mutant CRC patients and correlated with reduced overall survival. Functionally, ZBTB20 promoted CRC cell migration, invasion, EMT in vitro, and drove metastatic colonization in vivo. Mechanistically, KRAS/ERK signaling directly phosphorylated ZBTB20 at Threonine 138, 142, and 232, a step essential for its nuclear localization and pro-metastatic activity. Integrating transcriptomic and cistromic data, we identified TGFBR2 as a direct transcriptional target of activated ZBTB20. Notably, pharmacological degradation of TGFBR2 with the inhibitor ITD-1 potently abrogated metastatic outgrowth in both liver and lung colonization models.

Our findings delineate a novel KRAS-ERK-ZBTB20-TGFBR2 signaling axis that is a critical driver of metastasis colonization in KRAS-mutant CRC. The robust efficacy of a TGFBR2 degrader in multiple in vivo models validates this axis as a viable therapeutic target, offering a promising strategy to inhibit metastatic progression in patients with this aggressive disease.

The online version contains supplementary material available at 10.1186/s13046-025-03619-w.