The lack of presenting symptoms and subsequent late stage diagnosis of pancreatic ductal adenocarcinoma (PDAC) results in a cancer that is often surgically unresectable, locally advanced with a densely fibrotic stroma, and already spread to distant organs. The aggressive nature of this disease, coupled with systemic therapies that are largely ineffective, highlight the need for earlier diagnosis and new targeted therapies to improve patient outcomes.
c-Jun N-terminal Kinases (JNKs) mediate diverse cellular functions, with oncogenic roles described in numerous cancers, and opposing, tumour suppressive and apoptotic roles observed under homeostatic conditions. A significant body of research into JNK in triple negative breast cancer has revealed distinct, subcellular pools of JNK activity underlying these pleiotropic functions. This discovery prompted an investigation into whether similar patterns of subcellular JNK activity are observed and potentially targetable in PDAC. The data has demonstrated that while the dual JNK network states found within breast tissue differ from those seen in PDAC, the JNK signalling pathway remains an attractive therapeutic target.
Thorough in vitro and in vivo studies confirm that JNK activity in both the cytoplasm and nucleus drives proliferation and primary tumour growth in PDAC models. Together, these data suggest the likely presence of a single translocating pool of JNK, which regulates these functions by modulating nuclear transcription factors and the surrounding extracellular matrix, to promote metastatic progression. Indicating that direct JNK inhibitors targeting the oncogenic JNK signalling found in both the fibrotic primary tumour and during metastasis, could be an effective therapeutic strategy for patients.
More recent in vitro work using the anti-fibrotic direct JNK inhibitor, CC-90001, has convincingly demonstrated its ability to inhibit both proliferation and invasion. Alongside preliminary in vivo studies, which highlight its efficacy in a metastatic setting, CC-90001 is promising candidate for the treatment of pancreatic cancer.