TY - JOUR
T1 - Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated RAS signaling in driving tumorigenesis
AU - Martini, Miriam
AU - Russo, Mariangela
AU - Lamba, Simona
AU - Vitiello, Elisa
AU - Crowley, Emily Hannah
AU - Sassi, Francesco
AU - Romanelli, Davide
AU - Frattini, Milo
AU - Marchetti, Antonio
AU - Bardelli, Alberto
PY - 2013/3/15
Y1 - 2013/3/15
N2 - Colorectal cancers (CRC) are commonly classified into those with microsatellite instability and those that are microsatellite stable (MSS) but chromosomally unstable. The latter are characterized by poor prognosis and remain largely intractable at the metastatic stage. Comprehensive mutational analyses have revealed that the mixed lineage kinase 4 (MLK4) protein kinase is frequently mutated in MSS CRC with approximately 50% of the mutations occurring in KRAS- or BRAF-mutant tumors. This kinase has not been characterized previously and the relevance of MLK4 somatic mutations in oncogenesis has not been established. We report that MLK4-mutated alleles in CRC are constitutively active and increase the transformation and tumorigenic capacity of RAS-mutated cell lines. Gene expression silencing or targeted knockout of MLK4 impairs the oncogenic properties of KRAS- and BRAF-mutant cancer cells both in vitro and in xenograftmodels. In establishing the role of MLK4 in intracellular signaling, we show it directly phosphorylates MEK1 (MAP2K1) and that MEK/ERK (MAPK1) signaling is impaired in MLK4 knockout cells. These findings suggest that MLK4 inhibitors may be efficacious in KRAS- and BRAF-mutated CRCs and may provide a new opportunity for targeting such recalcitrant tumors.
AB - Colorectal cancers (CRC) are commonly classified into those with microsatellite instability and those that are microsatellite stable (MSS) but chromosomally unstable. The latter are characterized by poor prognosis and remain largely intractable at the metastatic stage. Comprehensive mutational analyses have revealed that the mixed lineage kinase 4 (MLK4) protein kinase is frequently mutated in MSS CRC with approximately 50% of the mutations occurring in KRAS- or BRAF-mutant tumors. This kinase has not been characterized previously and the relevance of MLK4 somatic mutations in oncogenesis has not been established. We report that MLK4-mutated alleles in CRC are constitutively active and increase the transformation and tumorigenic capacity of RAS-mutated cell lines. Gene expression silencing or targeted knockout of MLK4 impairs the oncogenic properties of KRAS- and BRAF-mutant cancer cells both in vitro and in xenograftmodels. In establishing the role of MLK4 in intracellular signaling, we show it directly phosphorylates MEK1 (MAP2K1) and that MEK/ERK (MAPK1) signaling is impaired in MLK4 knockout cells. These findings suggest that MLK4 inhibitors may be efficacious in KRAS- and BRAF-mutated CRCs and may provide a new opportunity for targeting such recalcitrant tumors.
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U2 - 10.1158/0008-5472.CAN-12-3074
DO - 10.1158/0008-5472.CAN-12-3074
M3 - Article
C2 - 23319808
AN - SCOPUS:84875425466
VL - 73
SP - 1912
EP - 1921
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -