Triple negative breast cancer (TNBC) patients have the worst outcomes of all breast cancer subtypes due to a lack of targeted therapies and high relapse rates with distant metastases. Given that metastases are the actual cause of death for these patients, there is an urgent need for the development of innovative approaches that specifically treat metastatic TNBC to improve patient outcomes.
The c-Jun N-terminal Kinase (JNK) has been identified as a central oncogenic signalling node in TNBC and crucial for metastatic disease progression. However, as JNK is also required to maintain the architecture of normal breast tissue and activate apoptosis in response to chemotherapeutic intervention, it is unlikely that broad-spectrum JNK inhibitors will yield clinical success. Preliminary data from our laboratory now demonstrate that these distinct cell behaviours are in fact controlled by two mutually exclusive and spatially discrete JNK signalling networks, with opposing functional and prognostic roles - a tumour suppressing, nuclear JNK pool, and an oncogenic, cytoplasmic JNK pool. As such, we have sought to resolve the cytoplasmic JNK signalling complex and by this, identify novel therapeutic strategies for the treatment of metastatic TNBC.
By adapting our in-house interaction-based proteomic platform, we have isolated the components of the cytoplasmic JNK complex. Utilising a targeted siRNA library and JNK activity biosensor coupled to high content imaging, we have identified the key scaffold protein that specifically drives oncogenic JNK signalling and validated its role across a panel of TNBC cell lines in 3D in vitro culture and in vivo metastasis models. Our data show that perturbing this key scaffold protein specifically inhibits the oncogenic forms of JNK, without disturbing its tumour suppressing or apoptotic functions. Further, scaffold depletion inhibits the growth of TNBC cells in vitro and impedes the outgrowth of TNBC metastases in vivo. These findings open up novel therapeutic options for targeting an oncogenic signalling node that is critical for the progression of metastatic TNBC.