DUSP4 knockdown in BRAF V600E mutant colorectal cancer induces cell cycle arrest and halts tumor growth

Abstract Oncogenic signaling in cancer cells is essential for proliferation, and its disruption, either through inhibition or overactivation, can provide therapeutic opportunities. Dual specificity phosphatase 4 (DUSP4), a negative regulator of the MAPK pathway that dephosphorylates ERK, has been proposed as a potential target; however, its therapeutic relevance has not been evaluated in vivo. In this study, we show that DUSP4 knock-down induces G1 cell cycle arrest and reduces proliferation in BRAFV600E-mutant and BRAF inhibitor-resistant colorectal cancer models, both in vitro and in vivo, and induces a rapid DUSP5-mediated adaptive response. While treatment achieved tumor stasis indicating disease control, it did not yield tumor regression, suggesting that DUSP4 may have limited efficacy as a monotherapy target in cancer. Competing Interest Statement All authors are full time employees at Boehringer Ingelheim RCV. Footnotes Competing interests All authors are full time employees at Boehringer Ingelheim RCV. Data availability The workflow for RNA-seq bioinformatics analyses is described in the Materials and Methods section. RNA sequencing data were uploaded to GEO under the accession number GSE289812 and will be made publicly available upon acceptance of this manuscript. All ARTi cell lines described in this study are available upon request.