Targeting the ATF4 pathway in cancer therapy

Introduction: Activating transcription factor 4 (ATF4) is a member of the activating transcription factor family. ATF4 expression is increased in response to a diverse array of microenvironmental stresses including amino acid depletion, oxidative stress and endoplasmic reticulum (ER) stress that are sensed by upstream eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinases. In tumours, ATF4 expression is detected in hypoxic- and nutrient-deprived regions where it promotes metabolic homeostasis and cancer cell survival by transcriptionally regulating amino acid uptake and biosynthesis, autophagy, redox balance and angiogenesis. Areas covered: The mechanism governing translational expression of ATF4 is discussed along with the physiological roles of ATF4 in growth and development. Conditions that result in ATF4 expression in tumours are described with a focus on the role of ATF4 in cancer progression and treatment resistance. Several approaches to target ATF4 are presented including strategies aimed at inhibiting transcriptional activity or increasing degradation, approaches to reduce ATF4 translation by inhibiting upstream eIF2 alpha kinases and targeting of downstream pathways that are regulated by ATF4 including amino acid biosynthesis, ER-associated degradation and autophagy. Expert opinion: The authors provide a number of suggestions that may assist in the development of ATF4 inhibitors.