Mixed Lineage Kinases (MLKs): Novel Mediators of Resistance to Targeted Therapies and MLK4 is a Novel Tumor Suppressor in Colon Cancer.

John Brognard, The University of Manchester, UK

Anna Marusiak, Zoe Edwards, Eleanor Trotter, Natalie Stephenson, Lorena Puto, Romina Girotti, Ricahrd Marais, Roger Lo, Tony Hunter, and Owen Samson, John Brognard

The MLKs are MAP3Ks that regulate both the JNK and p38 MAPK pathways. They directly phosphorylate MKK4/7 to activate the JNK pathway and MKK3/6 to activate the p38 pathway in response to extracellular stimuli, leading to regulation of a diverse array of cellular fates. We have recently demonstrated that all MLK family members are MEK kinases capable of activating the MEK/ERK pathway independent of the RAF kinases. Furthermore, we show that these kinases play a prevalent role in mediating resistance to targeted RAF inhibitor therapies in melanoma. More recently we have established MLK4 as a novel tumor suppressor harboring frequent loss-of-function mutations in colon cancer. We have elucidated the molecular mechanism by which MLK4 promotes inhibition of colon cancer proliferation, which is dependent upon abrogation of signaling in the MLK4-MKK7-JNK-cJUN-p21/p15 pathway. Lastly we provide evidence that loss of signaling in this pathway will likely work in concert with activating KRAS mutations to overcome oncogene-induced senescence and promote tumor growth.