Kinases are pivotal in cancer biology, acting as growth factor receptors, mediators of mitogen-activated pathways, and frequently as oncogenes. However, recent cancer genomics research has revealed that kinases can also function as tumor suppressors, offering new therapeutic avenues. One such kinase, MLK4, exhibits a complex and context-dependent role in various cancers. Identified as a highly mutated gene in metastatic solid tumors across multiple cancer types (PAN cancer), MLK4 promotes migration and invasion in breast cancer, modulates DNA damage response in triple-negative breast cancer (TNBC), and activates ERK and JNK pathways in colorectal cancer, driving tumorigenesis. Interestingly, MLK4 loss-of-function mutations can paradoxically suppress JNK signaling, enhancing colon tumorigenesis, while in glioblastoma, these mutations activate the NF-κB pathway, facilitating mesenchymal transition. This dual nature, where MLK4 can function as both a tumor suppressor and a promoter depending on the cancer type, underscores the need for a deeper mechanistic understanding.
Colorectal cancer, the third most common cancer worldwide, represents approximately 10% of all cancer cases and is the second leading cause of cancer-related deaths globally. Given the high prevalence of MLK4 mutations (about 7%) in this aggressive disease, it is vital to understand its role in this cancer. To achieve this, I am utilizing the dTAG system for targeted acute degradation of both wild-type MLK4 and its mutants within an isogenic cell line system. This strategy, coupled with proteomics and metabolomics analyses, aims to elucidate the regulatory networks linked to MLK4 and identify potential modulators of key signal transduction pathways. My research aims to provide critical insights into the complex functions of MLK4 in colorectal cancer, which could lead to the development of innovative therapeutic strategies.