Perspective Chapter: RNA Therapeutics for Cancers

RNA therapeutics represent a promising class of drugs and some of the successful therapeutics have been recently transformed into clinics for several disorders. A growing body of evidence has underlined the involvement of aberrant expression of cancer-associate genes or RNA splicing in the pathogenesis of a variety of cancers. In addition, there have been >200 clinical trials of oligonucleotide therapeutics targeting a variety of molecules in cancers. Although there are no approved RNA therapeutics against cancers so far, some promising outcomes have been obtained in phase 1/2 clinical trials. We will review the recent advances in the study of cancer pathogenesis associated with RNA therapeutics and the development of RNA therapeutics for cancers

Structural basis of cytokine-mediated activation of ALK family receptors

Anaplastic lymphoma kinase (ALK)(1) and the related leukocyte tyrosine kinase (LTK)(2) are recently deorphanized receptor tyrosine kinases(3). Together with their activating cytokines, ALKAL1 and ALKAL2(4-6) (also called FAM150A and FAM150B or AUG beta and AUG alpha, respectively), they are involved in neural development(7), cancer(7-9) and autoimmune diseases(10). Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain(11), consistent with a metabolic role for Drosophila ALK(12). Despite such functional pleiotropy and growing therapeutic relevance(13,14), structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases