Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer

Han Xiao; Rong Zhao; Wangyang Meng; Yongde Liao

doi:10.1016/j.jpha.2023.04.009

Volume 13 Issue 6

Jun. 2023

Turn off MathJax

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(6): 625-639

Han Xiao, Rong Zhao, Wangyang Meng, Yongde Liao. Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 625-639. doi: 10.1016/j.jpha.2023.04.009

Citation:

Han Xiao, Rong Zhao, Wangyang Meng, Yongde Liao. Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 625-639. doi: 10.1016/j.jpha.2023.04.009

Citation:

PDF( 6152 KB)

Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer

doi: 10.1016/j.jpha.2023.04.009

Han Xiao^{a
,
,},
Rong Zhao^a,
Wangyang Meng^b,
Yongde Liao^{a
,
,}

a. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China;
b. Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant No.: 82072593). We would like to thank the research team of Dr. Eliza Yankova, who initially synthesized STM2457 and published its structure. We are also grateful to Dr. Junho Choe and his research team for their pioneering work in the field of METTL3-mediated translation regulation.

Received Date: Dec. 23, 2022
Accepted Date: Apr. 13, 2023
Rev Recd Date: Mar. 24, 2023
Publish Date: Apr. 19, 2023

Abstract

Abstract

In non-small cell lung cancer (NSCLC), the heterogeneity promotes drug resistance, and the restricted expression of programmed death-ligand 1 (PD-L1) limits the immunotherapy benefits. Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like 3 (METTL3), the novel small-molecule inhibitor STM2457 is assumed to be useful for the treatment of NSCLC. We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression. Next, we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression. Importantly, we described the genome-wide characteristics of multiple omics data acquired from RNA sequencing, ribosome profiling, and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout. We also constructed a model for the regulation of the translation of METTL3 and PD-L1. Finally, we found PD-L1 upregulation by STM2457 in vivo and in vitro. In conclusion, STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome. Furthermore, it can improve the immunotherapy outcomes based on PD-L1 upregulation in NSCLC.
- STM2457,
- METTL3,
- Translatomics,
- Non-small cell lung cancer,
- PD-L1

FullText(HTML)

References(21)

References

H. Sung, J. Ferlay, R.L. Siegel, et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 71 (2021) 209-249.

Z. Chen, C.M. Fillmore, P.S. Hammerman, et al., Non-small-cell lung cancers: A heterogeneous set of diseases, Nat. Rev. Cancer 14 (2014) 535-546.

I. Dagogo-Jack, A.T. Shaw, Tumour heterogeneity and resistance to cancer therapies, Nat. Rev. Clin. Oncol. 15 (2018) 81-94.

M. Reck, J. Remon, M.D. Hellmann, First-line immunotherapy for non-small-cell lung cancer, J. Clin. Oncol. 40 (2022) 586-597.

M. Bhat, N. Robichaud, L. Hulea, et al., Targeting the translation machinery in cancer, Nat. Rev. Drug Discov. 14 (2015) 261-278.

J. Choe, S. Lin, W. Zhang, et al., mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis, Nature 561 (2018) 556-560.

C. Zeng, W. Huang, Y. Li, et al., Roles of METTL3 in cancer: Mechanisms and therapeutic targeting, J. Hematol. Oncol. 13 (2020), 117.

Z. Ni, P. Sun, J. Zheng, et al., JNK signaling promotes bladder cancer immune escape by regulating METTL3-mediated m6A modification of PD-L1 mRNA, Cancer Res. 82 (2022) 1789-1802.

E. Yankova, W. Blackaby, M. Albertella, et al., Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia, Nature 593 (2021) 597-601.

Q.-C. Xu, Y.C. Tien, Y.-H. Shi, et al., METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner, Oncogene 41 (2022) 1622-1633.

Z.-W. Zhang, X. Teng, F. Zhao, et al., METTL3 regulates m⁶A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma, Cell Rep. 41 (2022), 111530.

F. Loayza-Puch, K. Rooijers, L.C. Buil, et al., Tumour-specific proline vulnerability uncovered by differential ribosome codon reading, Nature 530 (2016) 490-494.

D. Leiser, B. Pochon, W. Blank-Liss, et al., Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation, FEBS Lett. 588 (2014) 653-658.

S.E. Bates, Epigenetic therapies for cancer, N. Engl. J. Med. 383 (2020) 650-663.

P.P. Chamberlain, L.G. Hamann, Development of targeted protein degradation therapeutics, Nat. Chem. Biol. 15 (2019) 937-944.

Q. Lan, P.Y. Liu, J. Haase, et al., The critical role of RNA m6A methylation in cancer, Cancer Res. 79 (2019) 1285-1292.

S. Lin, J. Choe, P. Du, et al., The m6A methyltransferase METTL3 promotes translation in human cancer cells, Mol. Cell 62 (2016) 335-345.

C. Sun, R. Mezzadra, T.N. Schumacher, Regulation and function of the PD-L1 checkpoint, Immunity 48 (2018) 434-452.

M. Wu, Q. Huang, Y. Xie, et al., Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation, J. Hematol. Oncol. 15 (2022), 24.

R. Yu, Y. Wei, C. He, et al., Integrative analyses of m6A regulators identify that METTL3 is associated with HPV status and immunosuppressive microenvironment in HPV-related cancers, Int. J. Biol. Sci. 18 (2022) 3874-3887.

H. Chen, Y. Pan, Q. Zhou, et al., METTL3 inhibits antitumor immunity by targeting m6A-BHLHE41-CXCL1/CXCR2 axis to promote colorectal cancer, Gastroenterology 163 (2022) 891-907.

Relative Articles

Supplements(0)

Cited By

Proportional views