Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS) G12C inhibitor that RAS gets rid of the title "undruggable". It is worth noting that the therapeutic effect of KRAS G12C inhibitors on different RAS allelic mutations or even different cancers with KRAS G12C varies significantly. Thus, deep understanding of the characteristics of each allelic RAS mutation will be a prerequisite for developing new RAS inhibitors. In this review, the structural and biochemical features of different RAS mutations are summarized and compared. Besides, the pathological characteristics and treatment responses of different cancers carrying RAS mutations are listed based on clinical reports. In addition, the development of RAS inhibitors, either direct or indirect, that target the downstream components in RAS pathway is summarized as well. Hopefully, this review will broaden our knowledge on RAS-targeting strategies and trigger more intensive studies on exploiting new RAS allele-specific inhibitors. K E Y W O R D Sallelic RAS mutation, cancer, personalized therapy, RAS inhibitor INTRODUCTIONRat sarcoma (RAS) proteins belong to the small-molecule G protein family. As binary molecular switch, RAS GTPases cycle between guanosine triphosphate (GTP)bound active form and guanosine diphosphate (GDP)bound inactive form, facilitating "on" or "off" state in signal transduction. There are three canonical RAS genes, kirsten-RAS (KRAS), neuroblastoma-RAS (NRAS), and harvey-RAS (HRAS), encoding four RAS proteins (KRAS4A, KRAS4B, NRAS, and HRAS). Among RAS

No abstract

Objectives Haploid germ cell-specific nuclear protein kinase (Haspin) is a serine/threonine kinase as an atypical kinase, which is structurally distinct from conventional protein kinases. Key findings Functionally, Haspin is involved in important cell cycle progression, particularly in critical mitosis regulating centromeric sister chromatid cohesion during prophase and prometaphase, and subsequently ensuring proper chromosome alignment during metaphase and the normal chromosome segregation during anaphase. However, increasing evidence has demonstrated that Haspin is significantly upregulated in a variety of cancer cells in addition to normal proliferating somatic cells. Its knockdown or small molecule inhibition could prevent cancer cell growth and induce apoptosis by disrupting the regular mitotic progression. Given the specificity of its expressed tissues or cells and the uniqueness of its current known substrate, Haspin can be a promising target against cancer. Consequently, selective synthetic and natural inhibitors of Haspin have been widely developed to determine their inhibitory power for various cancer cells in vivo and in vitro. Summary Here our perspective includes a comprehensive review of the roles and structure of Haspin, its relatively potent and selective inhibitors and Haspin’s preliminary studies in a variety of cancers.