Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation

Monica Pomaville; Mohansrinivas Chennakesavalu; Pingluan Wang; Zhiwei Jiang; Hui-Lung Sun; Peizhe Ren; Ryan Borchert; Varsha Gupta; Chang Ye; Ruiqi Ge; Zhongyu Zhu; Mallory Brodnik; Yuhao Zhong; Kelley Moore; Helen Salwen; Rani E George; Malgorzata Krajewska; Alexandre Chlenski; Mark A Applebaum; Chuan He; Susan L Cohn

doi:10.1016/j.celrep.2024.114165

Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation

Cell Rep. 2024 Apr 30;43(5):114165. doi: 10.1016/j.celrep.2024.114165. Online ahead of print.

Authors

Monica Pomaville¹, Mohansrinivas Chennakesavalu¹, Pingluan Wang², Zhiwei Jiang², Hui-Lung Sun², Peizhe Ren², Ryan Borchert¹, Varsha Gupta¹, Chang Ye², Ruiqi Ge², Zhongyu Zhu², Mallory Brodnik¹, Yuhao Zhong², Kelley Moore¹, Helen Salwen¹, Rani E George³, Malgorzata Krajewska⁴, Alexandre Chlenski¹, Mark A Applebaum¹, Chuan He⁵, Susan L Cohn⁶

Affiliations

¹ Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA.
² Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
³ Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ School of Biochemistry and Cell Biology, Biosciences Institute, University College Cork, Cork, Ireland.
⁵ Department of Chemistry, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, Il 60637 USA.
⁶ Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA. Electronic address: scohn@bsd.uchicago.edu.

PMID: 38691450
DOI: 10.1016/j.celrep.2024.114165

Abstract

The N⁶-methyladenosine (m⁶A) RNA modification is an important regulator of gene expression. m⁶A is deposited by a methyltransferase complex that includes methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14). High levels of METTL3/METTL14 drive the growth of many types of adult cancer, and METTL3/METTL14 inhibitors are emerging as new anticancer agents. However, little is known about the m⁶A epitranscriptome or the role of the METTL3/METTL14 complex in neuroblastoma, a common pediatric cancer. Here, we show that METTL3 knockdown or pharmacologic inhibition with the small molecule STM2457 leads to reduced neuroblastoma cell proliferation and increased differentiation. These changes in neuroblastoma phenotype are associated with decreased m⁶A deposition on transcripts involved in nervous system development and neuronal differentiation, with increased stability of target mRNAs. In preclinical studies, STM2457 treatment suppresses the growth of neuroblastoma tumors in vivo. Together, these results support the potential of METTL3/METTL14 complex inhibition as a therapeutic strategy against neuroblastoma.

Keywords: CP: Cancer; differentiation; epitranscriptome; gene expression regulation; m(6)A; neuroblastoma; therapeutic target; tumor growth.