Targeting the undruggable MYC in cancer: the rationale of using XPO1 inhibitors

MYC is an important transcription factor involved in physiological processes such as cell growth, proliferation and differentiation. However, aberrant MYC expression has oncogenic-driving potential and is observed in the majority of human cancers. XPO1 is a member of the exportin family of proteins which regulate protein and RNA export from the nucleus to the cytoplasm. XPO1 is aberrantly expressed in cancer, especially with the advancing of the disease. XPO1 inhibition is able to decrease MYC levels through various pathways leading to decreased cancer cell viability. These pathways include other undruggable targets such as p53 and KRAS, DNA damage repair proteins, immune response mediators including IκB, and other transcription factors such as eIF4E. Herein, we describe the potential pathways and mechanisms through which XPO1 inhibition promotes MYC downregulation and subsequent downregulation of its targets. We also describe possible drug combinations with potential clinical applications.