The highly metastatic, triple negative breast cancer (TNBC) subtype accounts for 15-20% of all breast cancer cases and has the worst clinical outcomes. Systemic chemotherapy remains the standard-of-care for TNBC, as no targeted therapies are available, although ~70% of patients do not achieve a pathological complete response to this treatment. Given that metastasis has likely occurred by the time many TNBC patients are diagnosed and treated, therapeutic strategies that can inhibit the growth and survival of disseminated tumour cells are urgently needed.
The c-Jun N-terminal Kinase (JNK) has long been considered a central oncogenic signalling and attractive drug target in TNBC, as well as a number of other cancer types. However, the challenge with directly targeting JNK using small molecule kinase inhibitors is that JNK can control a multitude of distinct and often opposing cell behaviours. For instance, while JNK is considered a potent oncogene in TNBC, it is also required to suppress tumour growth in normal breast tissue and activate apoptosis in response to cell stress and chemotherapeutic intervention. For clinical success, drugs targeting JNK signalling must discriminate between these functions and selectively inhibit oncogenic JNK activity, without perturbing tumour suppressor or apoptotic JNK functions.
Our work has now opened a path for therapeutic development in this field by demonstrating that two distinct JNK signalling network states exist simultaneously within breast cancer cells, with opposing functional and prognostic roles–a tumour suppressing nuclear JNK pool and an oncogenic cytosolic JNK pool, that is absent in normal tissue. We now demonstrate that the nuclear form of JNK is critical for maintaining normal breast tissue architecture, whilst cytoplasmic JNK is crucial for the metastatic outgrowth of disseminated TNBC cells. These data provided a rationale for our ongoing drug discovery program that has adopted a number of orthogonal approaches aimed at identifying novel drugs capable of specifically targeting metastatic TNBC through the selective inhibition of oncogenic JNK signalling.
New date: Thursday 11 August 2022
New location: 32.G01