c-Jun N-terminal kinases (JNKs) are critical regulators of diverse cellular 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 JNKs also maintain normal breast tissue architecture and mediate chemotherapy response, 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.
We have recently developed several tools to facilitate the investigation and targeting of oncogenic JNK in preclinical models of TNBC: 1) an inducible, genetically-encoded, localisation-specific JNK inhibitor that selectively inhibits cytoplasmic JNK; 2) a CRISPR-Cas9-mediated ablation of a key scaffold protein that we identified as an essential driver of the cytoplasmic JNK complex; 3) 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 investigate the mechanisms downstream of oncogenic JNK in TNBC. Through phosphoproteomic analyses and functional validation, we reveal high-confidence substrates and signalling networks that represent a novel therapeutic space to be explored. We anticipate that these findings will inform the development of novel therapies to target the oncogenic JNK network in TNBC.