Abstract A074: DUSP4 loss: A novel driver of colorectal cancer

Abstract The 5-year survival rate for metastatic colorectal cancer (CRC) is <14%, despite currently available treatments. Identification of new drivers of CRC progression is needed to improve patient outcomes. Genetic alterations that result in hyperactivation of the ERK pathway are a major driver of colorectal tumorigenesis, occurring at high frequency (>50%). While activating mutations of well-known oncogenes (ie. BRAF/RAS) have been identified, it is unknown whether additional unidentified genetic alterations may activate the ERK pathway. In particular, understanding of the occurrence and functional significance of genetic loss of ERK pathway negative regulators in CRC is limited. We examined the deletion frequency of major ERK pathway regulators in a TCGA cohort of 231 microsatellite stable colorectal cancers, and identified the critical negative regulator of ERK, dual-specificity phosphatase 4 (DUSP4) as a frequently deleted gene (∼48% of cases). Furthermore, DUSP4 deletion was associated with significantly lower DUSP4 expression. We hypothesized that DUSP4 deletion may be a mediator of enhanced ERK activation, and a previously unknown driver of colorectal cancer. To determine the functional role of DUSP4, we re-expressed DUSP4 in six CRC cell lines (with diverse genetic backgrounds) harboring DUSP4-deletion and minimal endogenous expression. In support of our hypothesis, DUSP4 re-expression resulted in suppressed ERK pathway output basally and upon EGF-stimulation, demonstrating its role as a critical ERK regulator in CRC cells. Furthermore, we observed accumulation of cells in G0-G1 phase, reduced proliferation and colony formation. Consistent with its tumour suppressive effect, DUSP4 re-expression was selected against during cell line expansion. These findings support the hypothesis that DUSP4 restrains ERK pathway activation and plays a tumour suppressive role in CRC. Validation of our findings in a novel mouse model is underway, where we will determine the role of Dusp4 deletion in colon homeostasis and tumorigenesis. Citation Format: Kristen A. Needham, Stan Kaczmarczyk, Fiona Chionh, Camilla M. Reehorst, Dmitri Mouradov, Laura J. Jenkins, Ian Y. Luk, Conor Kearney, Jack P. Collin, Oliver Sieber, John M. Mariadason. DUSP4 loss: A novel driver of colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A074.