c-Jun N-terminal kinases (JNKs) have critical roles in regulating diverse cell processes including proliferation, differentiation, and cell death. JNKs are hyperactivated in many cancers including triple-negative breast cancer (TNBC), where they have established roles in metastatic outgrowth, and are considered attractive therapeutic targets. However, as JNK also maintains normal breast tissue architecture and mediates apoptosis in response to chemotherapeutic agents, treatment with small-molecule JNK inhibitors is not clinically viable.
Our work has demonstrated that these opposing roles of JNK arise from two distinct, subcellular pools; a nuclear, tumour-suppressive form and a cytoplasmic, oncogenic form. Our data now reveal that it is the cytoplasmic JNK pool that specifically drives TNBC metastatic outgrowth, although the specific mechanisms underlying this are currently unknown.
Through our program of research, we have recently developed a number of tools to facilitate the investigation and targeting of oncogenic JNK in preclinical models of TNBC. The first uses an inducible, genetically-encoded, localisation-specific JNK inhibitor that specifically inhibits cytoplasmic JNK. A second model uses CRISPR-Cas9-mediated ablation of a key scaffold protein that we identified as an essential driver of the cytoplasmic JNK signalling complex. Finally, a third model uses a first-in-class oncogenic JNK inhibitor that we have identified through a process of phenotypic screening and ongoing drug development.
These models of cytoplasmic JNK inhibition will now be used to identify and characterise high-confidence substrates downstream of oncogenic JNK in TNBC. We anticipate that these findings will inform the development of novel therapies to target the oncogenic cytoplasmic JNK signalling node that is critical for progression of metastatic TNBC.