Decoding the Raf-Mek-Erk-Rsk pathway in prostate cancer: from molecular mechanisms to clinical opportunities

Advanced prostate cancer remains a major healthcare problem and cause of death in the United Kingdom. In contrast to many other cancer types, with the exception of poly (ADP-ribose) polymerase inhibition in DNA repair defective cancers, clinically actionable molecular subtypes are lacking. There are a number of studies that suggest the RAF-MEK-ERK-RSK cascade, a major oncogenic pathway, is activated in prostate cancer and this increases as the disease progresses. Mechanisms of activation are not dominated by pathogenic mutations in pathway proteins and include paracrine and autocrine mechanisms. There is strong evidence linking pathway activation with enhancing key proliferative signalling programmes and promoting cell survival in prostate cancer. Whilst inhibitors of the RAF-MEK-ERK-RSK pathway have demonstrated clinical utility in other cancers this has not been realised in prostate cancer. The reasons for this include a lack of predictive biomarkers for, and the unique landscape of pathway activation. Future studies need to identify robust predictive biomarkers, and improve the understanding of the fundamental biology of RAF-MEK-ERK-RSK activated prostate cancers if we are to successfully target this important sub-group.