Mixed-lineage Kinase 4 Interacts with Activated RAS Signaling in Colorectal Cancer

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Colorectal cancer that is microsatellite stable but chromosomally unstable is characterized by poor prognosis and remains largely intractable at the metastatic stage. Mutational analysis has shown that the mixed lineage kinase 4 (MLK4) protein kinase is frequently mutated in microsatellite-stable colorectal cancer, with approximately 50% of the mutations occurring in KRAS- or BRAF-mutant tumors. This kinase has not been characterized, and the potential role of MLK4 somatic mutations in oncogenesis has not been established.

Martini and colleagues recently reported that MLK4-mutated alleles in colorectal cancer are constitutively active and increase the transformation and tumorigenic capacity of RAS-mutated cell lines. Gene expression silencing and targeted knockout of MLK4 impaired the oncogenic activity of KRAS- and BRAF-mutant cancer cells both in vitro and in xenograft models. MLK4 was found to directly phosphorylate MEK1 (MAP2K1), with MEK/ERK (MAPK1) signaling being impaired in the MLK4 knockout cells.

The investigators concluded, “These findings suggest that MLK4 inhibitors may be efficacious in KRAS- and BRAF-mutated [colorectal cancers] and may provide a new opportunity for targeting such recalcitrant tumors.” ■

Martini M, Russo M, Lamba S, et al: Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated RAS signaling in driving tumorigenesis. Cancer Res 73:1912-1921, 2013.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.




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