RNA epitranscriptomics: A promising new avenue for cancer therapy
Authors: Chunlong Yang, Hui Han, Shuibin Lin
Journal: Molecular Therapy (2021)

Recently, Ipsen signed a $446 million collaboration agreement with Accent Therapeutics for the development and commercialization of a pre-clinical stage METTL3-inhibitor program to target cancers including acute myeloid leukemia (AML). METTL3 is an RNA-modifying protein (RMP) that catalyzes the N6-methyladenosine (m6A) modification on mRNAs. Emerging evidence demonstrates that METTL3 and other RMPs play crucial functions in RNA epitranscriptomic modifications and gene expression regulation. Misregulation of RMPs and their corresponding RNA modifications are closely linked with oncogenesis, suggesting that RMPs are promising therapeutic targets for cancer treatment. It has been more than 60 years since the first discovery of RNA modification.1Ontiveros R.J. Stoute J. Liu K.F. The chemical diversity of RNA modifications.Biochem. J. 2019; 476: 1227-1245Crossref PubMed Scopus (54) Google Scholar Over 170 different chemical modifications on different RNA species, including mRNA, tRNA, rRNA, small nuclear RNA (snRNA), and others, have been described and characterized.2Boccaletto P. Machnicka M.A. Purta E. Piatkowski P. Baginski B. Wirecki T.K. de Crécy-Lagard V. Ross R. Limbach P.A. Kotter A. et al.MODOMICS: a database of RNA modification pathways. 2017 update.Nucleic Acids Res. 2018; 46: D303-D307Crossref PubMed Scopus (1046) Google Scholar Recent studies revealed that RNA epitranscriptomic modifications are reversible and highly dynamic and are spatially and temporally regulated by numerous modifiers known as writer, eraser, and reader proteins. RNA modifications have diverse functions in RNA metabolism, including RNA maturation, structure, editing, stability, localization, translation, and so on. Thus, these diverse chemical modifications broadly impact gene expression and play important roles in various biological processes, including cell development and stem cell differentiation, as well as environmental responses. Dysregulations of RNA modification proteins reprogram the epitranscriptome and disrupt gene expression patterns, which in turn lead to disease development, including but not limited to human cancers. m6A is the most abundant chemical modification on mRNAs, and its functions in gene expression and cancers have been extensively studied in recent years. The m6A deposition is installed by the methyltransferase complex including METTL3 (active subunit), METTL14 (substrate-binding subunit), and accessory components (WTAP, KIAA1429, ZC3H13, and RBM15/RBM15B). Conversely, demethylases FTO and ALKBH5 (also called erasers) can remove m6A modifications on mRNAs. Specific m6A-binding proteins (also known as readers) recognize m6A-modified mRNAs and facilitate subsequent mRNA processing, metabolism, and translation. Studies from our group and others have revealed critical functions of m6A-related RMPs in the oncogenic transformation of various cancers.3Lin S. Choe J. Du P. Triboulet R. Gregory R.I. The m(6)A methyltransferase METTL3 promotes translation in human cancer cells.Mol. Cell. 2016; 62: 335-345Abstract Full Text Full Text PDF PubMed Scopus (864) Google Scholar,4Huang H. Weng H. Deng X. Chen J. RNA modifications in cancer: functions, mechanisms, and therapeutic implications.Annu. Rev. Cancer Biol. 2020; 4: 221-240Crossref Scopus (42) Google Scholar Thus, mRNA epitranscriptomic modifications represent a new layer of oncogenic mechanisms that regulate gene expression at the post-transcriptional level. Much effort has been made to screen for specific or selective chemical compounds that can inhibit the enzyme activities or other functions of RMPs. Recently, Huang and colleagues found that R-2HG, an analog of 2-oxoglutarate, inhibits FTO demethylase activity in vitro and in vivo and revealed that the FTO-specific inhibitor, FB23-2, displayed an effective therapeutic function in treating AML.5Su R. Dong L. Li C. Nachtergaele S. Wunderlich M. Qing Y. Deng X. Wang Y. Weng X. Hu C. et al.R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling.Cell. 2018; 172: 90-105.e23Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar,6Huang Y. Su R. Sheng Y. Dong L. Dong Z. Xu H. Ni T. Zhang Z.S. Zhang T. Li C. et al.Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia.Cancer Cell. 2019; 35: 677-691.e10Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar Another promising molecule, STM2457, was described as a first-in-class inhibitor of METTL3 in vitro and in vivo by Yankova and colleagues.7Yankova E. Blackaby W. Albertella M. Rak J. De Braekeleer E. Tsagkogeorga G. Pilka E.S. Aspris D. Leggate D. Hendrick A.G. et al.Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.Nature. 2021; 593: 597-601Crossref PubMed Scopus (204) Google Scholar This molecule inhibits the proliferation of AML cell lines and tumor formation in xenograft models of AML in a dose-dependent manner without toxicity to normal cells and tissues. A number of biopharmaceutical companies have recently been established to develop drugs targeting the epitranscriptomic machinery in cancer therapy. Accent Therapeutics is developing oncology-focused, small-molecule inhibitors of RMPs. The aforementioned collaboration agreement with Ipsen will expedite the development and commercialization of transformative oncology medicines targeting the m6A mRNA methytransferase METTL3 for cancer therapy. Gotham Therapeutics employs diverse small-molecule screening strategies coupled with state-of-the-art medicinal chemistry to develop inhibitors to target the epitranscriptomic machinery. Twentyeight-Seven Therapeutics works on developing small-molecule inhibitors of METTL3 and other RNA-binding proteins to target cancers. In addition, EPICS Therapeutics strives to develop small-molecule inhibitors to target RNA epigenetic mechanisms for cancer therapy. So far, about twenty nucleic acid drugs have received approval from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).8Gupta A. Andresen J.L. Manan R.S. Langer R. Nucleic acid delivery for therapeutic applications.Adv. Drug Deliv. Rev. 2021; 178: 113834https://doi.org/10.1016/j.addr.2021.113834Crossref PubMed Scopus (38) Google Scholar,9Kulkarni J.A. Witzigmann D. Thomson S.B. Chen S. Leavitt B.R. Cullis P.R. van der Meel R. The current landscape of nucleic acid therapeutics.Nat. Nanotechnol. 2021; 16: 630-643https://doi.org/10.1038/s41565-021-00898-0Crossref PubMed Scopus (178) Google Scholar Given that RNA-modification enzymes are frequently mis-regulated in cancers, nucleic acid therapeutics could be promising for targeting RNA epitranscriptomics in cancers. Although much progress has been achieved in recent years, there are also challenges remaining: (1) the detailed functions of over 170 distinct covalent modifications in the regulation of RNA processing and gene expression are still poorly understood, and new chemical alterations are still being discovered, including glycosylation; (2) RNA epitranscriptomic modifications are dynamically associated with various biological processes, and potential side effects of targeting the epitranscriptomic machinery must be further characterized; and (3) the same RMP could have either an oncogenic- or tumor-suppressive function in different cancer types or cellular contexts. Therefore, it is important to define the underlying molecular mechanisms when attempting personalized precision medicine. Thus, a further understanding of the molecular mechanisms underlying RNA epitranscriptomics in the regulation of cancers is essential for the development of novel therapeutic strategies.