DUSP4 knockdown in BRAF V600E mutant colorectal cancer induces cell cycle arrest and halts tumor growth
Hopfgartner, B.; Kriz, M.; Alpar, D.; Westermaier, Y.; Hofmann, M. H.; Neumuller, R. A.; Grosche, S.
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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.
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