The triple negative breast cancer (TNBC) subtype has a much poorer prognosis than hormone receptor or HER2 positive breast cancer, due in part to a higher relapse rate and frequent metastasis to the pleura, lung, liver and brain. The lack of clinically successful targeted therapies for TNBC means that chemotherapy remains the standard-of-care. To date, inhibitors to targets such as EGFR and c-MET have shown promising initial responses, followed by rapid relapse.
Therefore, instead of targeting individual molecules at the top of signalling pathways, we hypothesise that inhibiting the key nodes that integrate signalling from many potential oncogenes will be a more efficient strategy. To this end, we have identified JNK as a critical oncogenic signalling node within TNBC cells, which conveys signals from multiple oncogenic pathways to promote proliferation, invasion and metastasis.
Due to the necessity of JNK for many normal processes, tumour suppression and chemotherapy response in other tissues, systemically targeting JNK is unlikely to yield successful translation to the clinic. Instead we now demonstrate that two distinct JNK network states exist simultaneously within breast cancer cells, with opposing functional and prognostic roles. Through studies of patient cohorts, and the use of genetically encoded localization-specific JNK inhibitors within three-dimensional cell culture models and in vivo metastasis assays, we show that these two network states are spatially separated into a tumour suppressing, nuclear JNK pool, and an oncogenic, cytosolic JNK pool.
By adapting our recently published, interaction-based proteomic platform (Croucher et al., Science Signaling, 2016) we have specifically isolated and characterised the oncogenic, cytosolic JNK complex. We also demonstrate that perturbing this signalling complex can specifically inhibit the oncogenic form of JNK, without disturbing the tumour suppressing function of nuclear JNK activity. This finding therefore opens up novel therapeutic options for targeting this critical oncogenic signalling node in TNBC.