Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Cancer Therapy Reviews
  4. Fast Track Articles
  5. Fast Track Article
image of Exploring the Function of METTL3 in Lung Cancer: Understanding Drug Resistance and Exploring Innovative Therapeutic Approaches

Abstract

Globally, lung cancer continues to be the primary cause of cancer-related fatalities. Despite significant advancements in chemotherapy, targeted therapy, and immunotherapy that have improved treatment effectiveness and increased survival rates, the five-year relative survival rate for lung cancer patients remains very low. Most cases receive a diagnosis at an advanced stage, which primarily contributes to this. Drug resistance is still a significant challenge, which is responsible for 90% of cancer-related deaths. Epigenetic alterations, including DNA methylation, RNA modification, and histone modification, play crucial roles in cancer treatment resistance. Among these, the methyltransferase-like 3 (METTL3)-induced N6-methyladenosine (m6A) RNA modification has received a lot of attention because it plays a part in lung cancer tumor growth, carcinogenesis, proliferation, and resistance to treatment. Researchers have identified or developed several METTL3 inhibitors that have shown promising therapeutic benefits in both and models. This review focuses on the progress that has been made in the research investigating the role of METTL3 in lung cancer treatment resistance. It also elucidates the processes that are at play and investigates prospective therapeutic options that target METTL3 in order to enhance treatment results and overcome drug resistance.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cctr/10.2174/0115733947364895250307042821
2025-03-12
2025-05-06

  • From This Site

    /content/journals/cctr/10.2174/0115733947364895250307042821
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Bray F. Laversanne M. Sung H. Ferlay J. Siegel R.L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024 74 3 229 263 10.3322/caac.21834 38572751
    [Google Scholar]
  2. Cronin K.A. Lake A.J. Scott S. Sherman R.L. Noone A.M. Howlader N. Henley S.J. Anderson R.N. Firth A.U. Ma J. Kohler B.A. Jemal A. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer 2018 124 13 2785 2800 10.1002/cncr.31551 29786848
    [Google Scholar]
  3. Fontana D. Crespiatico I. Crippa V. Malighetti F. Villa M. Angaroni F. De Sano L. Aroldi A. Antoniotti M. Caravagna G. Piazza R. Graudenzi A. Mologni L. Ramazzotti D. Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients. Nat. Commun. 2023 14 1 5982 10.1038/s41467‑023‑41670‑3 37749078
    [Google Scholar]
  4. Bukowski K. Kciuk M. Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci. 2020 21 9 3233 10.3390/ijms21093233 32370233
    [Google Scholar]
  5. Xie B. Peng F. He F. Cheng Y. Cheng J. Zhou Z. Mao W. DNA methylation influences the CTCF‐modulated transcription of RASSF1A in lung cancer cells. Cell Biol. Int. 2022 46 11 1900 1914 10.1002/cbin.11868 35989484
    [Google Scholar]
  6. Reid T.R. Merigan T.C. Basham T. Resistance to interferon-α in a mouse B-cell lymphoma involves DNA methylation. J. Interferon Res. 1992 12 2 131 137 10.1089/jir.1992.12.131 1374455
    [Google Scholar]
  7. Uddin M.B. Roy K.R. Hosain S.B. Khiste S.K. Hill R.A. Jois S.D. Zhao Y. Tackett A.J. Liu Y.Y. An N. An N-methyladenosine at the transited codon 273 of p53 pre-mRNA promotes the expression of R273H mutant protein and drug resistance of cancer cells. Biochem. Pharmacol. 2019 160 134 145 10.1016/j.bcp.2018.12.014 30578766
    [Google Scholar]
  8. Chen Q. Yang B. Liu X. Zhang X.D. Zhang L. Liu T. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Theranostics 2022 12 11 4935 4948 10.7150/thno.73223 35836809
    [Google Scholar]
  9. Yu R. Wei Y. He C. Zhou P. Yang H. Deng C. Liu R. Wu P. Gao Q. Cao C. Integrative analyses of m6A regulators identify that METTL3 is associated with HPV status and immunosuppressive microenvironment in HPV-related cancers. Int. J. Biol. Sci. 2022 18 9 3874 3887 10.7150/ijbs.70674 35813476
    [Google Scholar]
  10. Gan H. Hong L. Yang F. Liu D. Jin L. Zheng Q. Progress in epigenetic modification of mRNA and the function of m6A modification. Chin. J. Biotechnol. 2019 35 5 775 783 31222996
    [Google Scholar]
  11. Jiang X. Liu B. Nie Z. Duan L. Xiong Q. Jin Z. Yang C. Chen Y. The role of m6A modification in the biological functions and diseases. Signal Transduct. Target. Ther. 2021 6 1 74 74 10.1038/s41392‑020‑00450‑x 33611339
    [Google Scholar]
  12. Wang S. Fan X. Zhu J. Xu D. Li R. Chen R. Hu J. Shen Y. Hao J. Wang K. Jiang X. Wang Y. Jiang Y. Li J. Zhang J. The differentiation of colorectal cancer is closely relevant to m6A modification. Biochem. Biophys. Res. Commun. 2021 546 65 73 10.1016/j.bbrc.2021.02.001 33571906
    [Google Scholar]
  13. Liu S. Zhuo L. Wang J. Zhang Q. Li Q. Li G. Yan L. Jin T. Pan T. Sui X. Lv Q. Xie T. METTL3 plays multiple functions in biological processes. Am. J. Cancer Res. 2020 10 6 1631 1646 32642280
    [Google Scholar]
  14. Deng L.J. Deng W.Q. Fan S.R. Chen M.F. Qi M. Lyu W.Y. Qi Q. Tiwari A.K. Chen J.X. Zhang D.M. Chen Z.S. m6A modification: Recent advances, anticancer targeted drug discovery and beyond. Mol. Cancer 2022 21 1 52 52 10.1186/s12943‑022‑01510‑2 35164788
    [Google Scholar]
  15. Han J. Wang J. Yang X. Yu H. Zhou R. Lu H.C. Yuan W.B. Lu J. Zhou Z. Lu Q. Wei J.F. Yang H. METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol. Cancer 2019 18 1 110 110 10.1186/s12943‑019‑1036‑9 31228940
    [Google Scholar]
  16. Hu C. Liu J. Li Y. Jiang W. Ji D. Liu W. Ma T. Multifaceted roles of the N(6)-methyladenosine RNA methyltransferase METTL3 in cancer and immune microenvironment. Biomolecules 2022 12 8 1042 10.3390/biom12081042 36008936
    [Google Scholar]
  17. Wang L. Yang Q. Zhou Q. Fang F. Lei K. Liu Z. Zheng G. Zhu L. Huo J. Li X. Peng S. Kuang M. Lin S. Huang M. Xu L. METTL3-m6A-EGFR-axis drives lenvatinib resistance in hepatocellular carcinoma. Cancer Lett. 2023 559 216122 10.1016/j.canlet.2023.216122 36898427
    [Google Scholar]
  18. Wang Q. Chen C. Ding Q. Zhao Y. Wang Z. Chen J. Jiang Z. Zhang Y. Xu G. Zhang J. Zhou J. Sun B. Zou X. Wang S. METTL3-mediated m 6 A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut 2020 69 7 1193 1205 10.1136/gutjnl‑2019‑319639 31582403
    [Google Scholar]
  19. Xu Y. Song M. Hong Z. Chen W. Zhang Q. Zhou J. Yang C. He Z. Yu J. Peng X. Zhu Q. Li S. Ji K. Liu M. Zuo Q. The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer. J. Exp. Clin. Cancer Res. 2023 42 1 10 10 10.1186/s13046‑022‑02581‑1 36609396
    [Google Scholar]
  20. Śledź P. Jinek M. Structural insights into the molecular mechanism of the m6A writer complex. eLife 2016 5 e18434 10.7554/eLife.18434 27627798
    [Google Scholar]
  21. Xiao H. Zhao R. Meng W. Liao Y. Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer. J. Pharm. Anal. 2023 13 6 625 639 10.1016/j.jpha.2023.04.009 37440912
    [Google Scholar]
  22. Huang H. Camats-Perna J. Medeiros R. Anggono V. Widagdo J. Altered expression of the m6A methyltransferase METTL3 in Alzheimer's disease. eNeuro 2020 7 5 ENEURO.0125-20.2020 10.1523/ENEURO.0125‑20.2020
    [Google Scholar]
  23. Zhang X. Li X. Jia H. An G. Ni J. The m6A methyltransferase METTL3 modifies PGC-1α mRNA promoting mitochondrial dysfunction and oxLDL-induced inflammation in monocytes. J. Biol. Chem. 2021 297 3 101058 101058 10.1016/j.jbc.2021.101058 34375639
    [Google Scholar]
  24. Cui X. Nilsson K. Kajitani N. Schwartz S. Overexpression of m6A-factors METTL3, ALKBH5, and YTHDC1 alters HPV16 mRNA splicing. Virus Genes 2022 58 2 98 112 10.1007/s11262‑022‑01889‑6 35190939
    [Google Scholar]
  25. Li H. Xiao W. He Y. Wen Z. Cheng S. Zhang Y. Li Y. Novel insights into the multifaceted functions of RNA n(6)-methyladenosine modification in degenerative musculoskeletal diseases. Front. Cell Dev. Biol. 2021 9 766020 766020 10.3389/fcell.2021.766020 35024366
    [Google Scholar]
  26. Wu X. Ye W. Gong Y. The role of RNA methyltransferase METTL3 in normal and malignant hematopoiesis. Front. Oncol. 2022 12 873903 873903 10.3389/fonc.2022.873903 35574332
    [Google Scholar]
  27. Fang X. Li M. Yu T. Liu G. Wang J. Reversible N6-methyladenosine of RNA: The regulatory mechanisms on gene expression and implications in physiology and pathology. Genes Dis. 2020 7 4 585 597 10.1016/j.gendis.2020.06.011 33335958
    [Google Scholar]
  28. Peng C. Xiong F. Pu X. Hu Z. Yang Y. Qiao X. Jiang Y. Han M. Wang D. Li X. m6A methylation modification and immune cell infiltration: implications for targeting the catalytic subunit m6A-METTL complex in gastrointestinal cancer immunotherapy. Front. Immunol. 2023 14 1326031 1326031 10.3389/fimmu.2023.1326031 38187373
    [Google Scholar]
  29. Huang J. Dong X. Gong Z. Qin L.Y. Yang S. Zhu Y.L. Wang X. Zhang D. Zou T. Yin P. Tang C. Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferase. Protein Cell 2019 10 4 272 284 10.1007/s13238‑018‑0518‑7 29542011
    [Google Scholar]
  30. Wang P. Doxtader K.A. Nam Y. Structural basis for cooperative function of Mettl3 and Mettl14 Methyltransferases. Mol. Cell 2016 63 2 306 317 10.1016/j.molcel.2016.05.041 27373337
    [Google Scholar]
  31. Jin Q. Qu H. Quan C. New insights into the regulation of METTL3 and its role in tumors. Cell Commun. Signal. 2023 21 1 334 334 10.1186/s12964‑023‑01360‑5 37996892
    [Google Scholar]
  32. Sun J. Cheng B. Su Y. Li M. Ma S. Zhang Y. Zhang A. Cai S. Bao Q. Wang S. Zhu P. The potential role of m6A RNA methylation in the aging process and aging-associated diseases. Front. Genet. 2022 13 869950 10.3389/fgene.2022.869950 35518355
    [Google Scholar]
  33. Bokar J.A. Rath-Shambaugh M.E. Ludwiczak R. Narayan P. Rottman F. Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J. Biol. Chem. 1994 269 26 17697 17704 10.1016/S0021‑9258(17)32497‑3 8021282
    [Google Scholar]
  34. Huang Q. Mo J. Liao Z. Chen X. Zhang B. The RNA m6A writer WTAP in diseases: Structure, roles, and mechanisms. Cell Death Dis. 2022 13 10 852 852 10.1038/s41419‑022‑05268‑9 36207306
    [Google Scholar]
  35. Qi L. Yin Y. Sun M. m6A-mediated lncRNA NEAT1 plays an oncogenic role in non-small cell lung cancer by upregulating the HMGA1 expression through binding miR-361-3p. Genes Genomics 2023 45 12 1537 1547 10.1007/s13258‑023‑01442‑1 37688756
    [Google Scholar]
  36. Zhang Q. Zhang Y. Chen H. Sun L.N. Zhang B. Yue D.S. Wang C.L. Zhang Z.F. METTL3-induced DLGAP1-AS2 promotes non-small cell lung cancer tumorigenesis through m 6 A/c-Myc-dependent aerobic glycolysis. Cell Cycle 2022 21 24 2602 2614 10.1080/15384101.2022.2105885 35972892
    [Google Scholar]
  37. Li W.H. Dang Y. Zhang L. Zhou J.C. Zhai H.Y. Yang Z. Ma K. Wang Z.Z. METTL3-mediated m6A methylation of DNMT1 promotes the progression of non-small cell lung cancer by regulating the DNA methylation of FOXO3a. Heliyon 2024 10 7 e28618 e28618 10.1016/j.heliyon.2024.e28618 38586389
    [Google Scholar]
  38. He G. Gu K. Wei J. Zhang J. METTL3 ‐mediated the m6A modification of SF3B4 facilitates the development of non‐small cell lung cancer by enhancing LSM4 expression. Thorac. Cancer 2024 15 11 919 928 10.1111/1759‑7714.15275 38462740
    [Google Scholar]
  39. Shi L. Gong Y. Zhuo L. Wang S. Chen S. Ke B. Methyltransferase-like 3 upregulation is involved in the chemoresistance of non-small cell lung cancer. Ann. Transl. Med. 2022 10 3 139 139 10.21037/atm‑21‑6608 35284536
    [Google Scholar]
  40. Rosell R. Gatzemeier U. Betticher D.C. Keppler U. Macha H.N. Pirker R. Berthet P. Breau J.L. Lianes P. Nicholson M. Ardizzoni A. Chemaissani A. Bogaerts J. Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: A cooperative multinational trial. Ann. Oncol. 2002 13 10 1539 1549 10.1093/annonc/mdf332 12377641
    [Google Scholar]
  41. Scagliotti G.V. Parikh P. von Pawel J. Biesma B. Vansteenkiste J. Manegold C. Serwatowski P. Gatzemeier U. Digumarti R. Zukin M. Lee J.S. Mellemgaard A. Park K. Patil S. Rolski J. Goksel T. de Marinis F. Simms L. Sugarman K.P. Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J. Clin. Oncol. 2023 41 14 2458 2466 10.1200/JCO.22.02544 37146426
    [Google Scholar]
  42. Sun Y. Shen W. Hu S. Lyu Q. Wang Q. Wei T. Zhu W. Zhang J. METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy. J. Exp. Clin. Cancer Res. 2023 42 1 65 65 10.1186/s13046‑023‑02638‑9 36932427
    [Google Scholar]
  43. Wang Y. Ren H. Multi-omics sequencing revealed endostar combined with cisplatin treated non small cell lung cancer via anti-angiogenesis. BMC Cancer 2024 24 1 187 187 10.1186/s12885‑023‑11665‑w 38331776
    [Google Scholar]
  44. Dong H. Zeng L. Chen W. Zhang Q. Wang F. Wu Y. Cui B. Qi J. Zhang X. Liu C. Deng J. Yu Y. Schmitt C.A. Du J. N6-methyladenine-mediated aberrant activation of the lncRNA SOX2OT-GLI1 loop promotes non-small-cell lung cancer stemness. Cell Death Discov. 2023 9 1 149 149 10.1038/s41420‑023‑01442‑w 37149646
    [Google Scholar]
  45. Théry C. Zitvogel L. Amigorena S. Exosomes: Composition, biogenesis and function. Nat. Rev. Immunol. 2002 2 8 569 579 10.1038/nri855 12154376
    [Google Scholar]
  46. Zhang L. Yu D. Exosomes in cancer development, metastasis, and immunity. Biochim. Biophys. Acta Rev. Cancer 2019 1871 2 455 468 10.1016/j.bbcan.2019.04.004 31047959
    [Google Scholar]
  47. Xie H. Yao J. Wang Y. Ni B. Exosome-transmitted circVMP1 facilitates the progression and cisplatin resistance of non-small cell lung cancer by targeting miR-524-5p-METTL3/SOX2 axis. Drug Deliv. 2022 29 1 1257 1271 10.1080/10717544.2022.2057617 35467477
    [Google Scholar]
  48. Qin X. Yu S. Xu X. Shen B. Feng J. Comparative analysis of microRNA expression profiles between A549, A549/DDP and their respective exosomes. Oncotarget 2017 8 26 42125 42135 10.18632/oncotarget.15009 28178672
    [Google Scholar]
  49. Ebrahimi S.O. Reiisi S. Downregulation of miR-4443 and miR-5195-3p in ovarian cancer tissue contributes to metastasis and tumorigenesis. Arch. Gynecol. Obstet. 2019 299 5 1453 1458 10.1007/s00404‑019‑05107‑x 30810880
    [Google Scholar]
  50. Gao Y. Xu Y. Wang J. Yang X. Wen L. Feng J. lncRNA MNX1-AS1 promotes glioblastoma progression through inhibition of miR-4443. Oncol. Res. 2019 27 3 341 347 10.3727/096504018X15228909735079 29678219
    [Google Scholar]
  51. Song Z. Jia G. Ma P. Cang S. Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis. Life Sci. 2021 276 119399 10.1016/j.lfs.2021.119399 33781830
    [Google Scholar]
  52. Eno M.S. Brubaker J.D. Campbell J.E. De Savi C. Guzi T.J. Williams B.D. Wilson D. Wilson K. Brooijmans N. Kim J. Özen A. Perola E. Hsieh J. Brown V. Fetalvero K. Garner A. Zhang Z. Stevison F. Woessner R. Singh J. Timsit Y. Kinkema C. Medendorp C. Lee C. Albayya F. Zalutskaya A. Schalm S. Dineen T.A. Discovery of BLU-945, a reversible, potent, and wild-type-sparing next-generation EGFR mutant inhibitor for treatment-resistant non-small-cell lung cancer. J. Med. Chem. 2022 65 14 9662 9677 10.1021/acs.jmedchem.2c00704 35838760
    [Google Scholar]
  53. Ramalingam S.S. Vansteenkiste J. Planchard D. Cho B.C. Gray J.E. Ohe Y. Zhou C. Reungwetwattana T. Cheng Y. Chewaskulyong B. Shah R. Cobo M. Lee K.H. Cheema P. Tiseo M. John T. Lin M.C. Imamura F. Kurata T. Todd A. Hodge R. Saggese M. Rukazenkov Y. Soria J.C. FLAURA Investigators Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N. Engl. J. Med. 2020 382 1 41 50 10.1056/NEJMoa1913662 31751012
    [Google Scholar]
  54. Soria J.C. Ohe Y. Vansteenkiste J. Reungwetwattana T. Chewaskulyong B. Lee K.H. Dechaphunkul A. Imamura F. Nogami N. Kurata T. Okamoto I. Zhou C. Cho B.C. Cheng Y. Cho E.K. Voon P.J. Planchard D. Su W.C. Gray J.E. Lee S.M. Hodge R. Marotti M. Rukazenkov Y. Ramalingam S.S. FLAURA Investigators Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N. Engl. J. Med. 2018 378 2 113 125 10.1056/NEJMoa1713137 29151359
    [Google Scholar]
  55. Gao F. Wang Q. Zhang C. Zhang C. Qu T. Zhang J. Wei J. Guo R. RNA methyltransferase METTL3 induces intrinsic resistance to gefitinib by combining with MET to regulate PI3K/AKT pathway in lung adenocarcinoma. J. Cell. Mol. Med. 2021 25 5 2418 2425 10.1111/jcmm.16114 33491264
    [Google Scholar]
  56. Zhang H. Wang S.Q. Wang L. Lin H. Zhu J.B. Chen R. Li L.F. Cheng Y.D. Duan C.J. Zhang C.F. m6A methyltransferase METTL3-induced lncRNA SNHG17 promotes lung adenocarcinoma gefitinib resistance by epigenetically repressing LATS2 expression. Cell Death Dis. 2022 13 7 657 657 10.1038/s41419‑022‑05050‑x 35902569
    [Google Scholar]
  57. Liu S. Li Q. Li G. Zhang Q. Zhuo L. Han X. Zhang M. Chen X. Pan T. Yan L. Jin T. Wang J. Lv Q. Sui X. Xie T. The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene. Cell Death Dis. 2020 11 11 969 10.1038/s41419‑020‑03148‑8 33177491
    [Google Scholar]
  58. Dai J. Qu T. Yin D. Cui Y. Zhang C. Zhang E. Guo R. LncRNA LINC00969 promotes acquired gefitinib resistance by epigenetically suppressing of NLRP3 at transcriptional and posttranscriptional levels to inhibit pyroptosis in lung cancer. Cell Death Dis. 2023 14 5 312 312 10.1038/s41419‑023‑05840‑x 37156816
    [Google Scholar]
  59. Ji Y. Zhao Q. Feng W. Peng Y. Hu B. Chen Q. N6-methyladenosine modification of CIRCKRT17 initiated by METTL3 promotes osimertinib resistance of lung adenocarcinoma by EIF4A3 to enhance YAP1 stability. Cancers 2022 14 22 5582 10.3390/cancers14225582 36428672
    [Google Scholar]
  60. Li K. Gao S. Ma L. Sun Y. Peng Z.Y. Wu J. Du N. Ren H. Tang S.C. Sun X. Stimulation of Let-7 maturation by metformin improved the response to tyrosine kinase inhibitor therapy in an m6A dependent manner. Front. Oncol. 2022 11 731561 731561 10.3389/fonc.2021.731561 35070958
    [Google Scholar]
  61. Hotta K. Hida T. Nokihara H. Morise M. Kim Y.H. Azuma K. Seto T. Takiguchi Y. Nishio M. Yoshioka H. Kumagai T. Watanabe S. Goto K. Satouchi M. Kozuki T. Shukuya T. Nakagawa K. Mitsudomi T. Yamamoto N. Asakawa T. Yoshimoto T. Takata S. Tamura T. Final overall survival analysis from the phase III J-ALEX study of alectinib versus crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive non-small-cell lung cancer. ESMO Open 2022 7 4 100527 100527 10.1016/j.esmoop.2022.100527 35843080
    [Google Scholar]
  62. Solomon B.J. Bauer T.M. Mok T.S.K. Liu G. Mazieres J. de Marinis F. Goto Y. Kim D.W. Wu Y.L. Jassem J. López F.L. Soo R.A. Shaw A.T. Polli A. Messina R. Iadeluca L. Toffalorio F. Felip E. Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: Updated analysis of data from the phase 3, randomised, open-label CROWN study. Lancet Respir. Med. 2023 11 4 354 366 10.1016/S2213‑2600(22)00437‑4 36535300
    [Google Scholar]
  63. Camidge D.R. Otterson G.A. Clark J.W. Ignatius Ou S.H. Weiss J. Ades S. Shapiro G.I. Socinski M.A. Murphy D.A. Conte U. Tang Y. Wang S.C. Wilner K.D. Villaruz L.C. Crizotinib in patients with MET-amplified NSCLC. J. Thorac. Oncol. 2021 16 6 1017 1029 10.1016/j.jtho.2021.02.010 33676017
    [Google Scholar]
  64. Ding N. You A. Tian W. Gu L. Deng D. Chidamide increases the sensitivity of non-small cell lung cancer to Crizotinib by decreasing c- MET mRNA methylation. Int. J. Biol. Sci. 2020 16 14 2595 2611 10.7150/ijbs.45886 32792859
    [Google Scholar]
  65. Reck M. Rodríguez-Abreu D. Robinson A.G. Hui R. Csőszi T. Fülöp A. Gottfried M. Peled N. Tafreshi A. Cuffe S. O’Brien M. Rao S. Hotta K. Leiby M.A. Lubiniecki G.M. Shentu Y. Rangwala R. Brahmer J.R. KEYNOTE-024 Investigators Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N. Engl. J. Med. 2016 375 19 1823 1833 10.1056/NEJMoa1606774 27718847
    [Google Scholar]
  66. Zhou Y. Zhang Y. Guo G. Cai X. Yu H. Cai Y. Zhang B. Hong S. Zhang L. Nivolumab plus ipilimumab versus pembrolizumab as chemotherapy‐free, first‐line treatment for PD‐L1‐positive non‐small cell lung cancer. Clin. Transl. Med. 2020 10 1 107 115 10.1002/ctm2.14 32508007
    [Google Scholar]
  67. Bai R. Chen N. Li L. Du N. Bai L. Lv Z. Tian H. Cui J. Mechanisms of cancer resistance to immunotherapy. Front. Oncol. 2020 10 1290 1290 10.3389/fonc.2020.01290 32850400
    [Google Scholar]
  68. Lee H.L. Tsai Y.C. Pikatan N.W. Yeh C.T. Yadav V.K. Chen M.Y. Tsai J.T. Tumor-associated macrophages affect the tumor microenvironment and radioresistance via the upregulation of CXCL6/CXCR2 in hepatocellular carcinoma. Biomedicines 2023 11 7 2081 10.3390/biomedicines11072081 37509721
    [Google Scholar]
  69. Li Y. Shen Z. Chai Z. Zhan Y. Zhang Y. Liu Z. Liu Y. Li Z. Lin M. Zhang Z. Liu W. Guan S. Zhang J. Qian J. Ding Y. Li G. Fang Y. Deng H. Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity. Gut 2023 72 12 2307 2320 10.1136/gutjnl‑2022‑329147 37507218
    [Google Scholar]
  70. Yang K. Xie Y. Xue L. Li F. Luo C. Liang W. Zhang H. Li Y. Ren Y. Zhao M. Wang W. Liu J. Shen X. Zhou W. Fei J. Chen W. Gu W. Wang L. Li F. Hu J. M2 tumor-associated macrophage mediates the maintenance of stemness to promote cisplatin resistance by secreting TGF-β1 in esophageal squamous cell carcinoma. J. Transl. Med. 2023 21 1 26 26 10.1186/s12967‑022‑03863‑0 36641471
    [Google Scholar]
  71. Zheng N. Wang T. Luo Q. Liu Y. Yang J. Zhou Y. Xie G. Ma Y. Yuan X. Shen L. M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance. OncoImmunology 2023 12 1 2210959 2210959 10.1080/2162402X.2023.2210959 37197441
    [Google Scholar]
  72. Wu L. Cheng D. Yang X. Zhao W. Fang C. Chen R. Ji M. M2-TAMs promote immunoresistance in lung adenocarcinoma by enhancing METTL3-mediated m6A methylation. Ann. Transl. Med. 2022 10 24 1380 1380 10.21037/atm‑22‑6104 36660648
    [Google Scholar]
  73. Sun Z. Mai H. Xue C. Fan Z. Li J. Chen H. Huo N. Kang X. Tang C. Fang L. Zhao H. Han Y. Sun C. Peng H. Du Y. Yang J. Du N. Xu X. Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination. J. Immunother. Cancer 2023 11 12 e007415 10.1136/jitc‑2023‑007415 38040417
    [Google Scholar]
  74. Liu Z. Wang T. She Y. Wu K. Gu S. Li L. Dong C. Chen C. Zhou Y. N6-methyladenosine-modified circIGF2BP3 inhibits CD8+ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer. Mol. Cancer 2021 20 1 105 105 10.1186/s12943‑021‑01398‑4 34416901
    [Google Scholar]
  75. Dong Y. Chen J. Chen Y. Liu S. Targeting the STAT3 oncogenic pathway: Cancer immunotherapy and drug repurposing. Biomed. Pharmacother. 2023 167 115513 10.1016/j.biopha.2023.115513 37741251
    [Google Scholar]
  76. Zhou X. Li C. Chen T. Li W. Wang X. Yang Q. Targeting R.N.A. Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy. Mol. Cancer 2023 22 1 36 36 10.1186/s12943‑023‑01746‑6 36810108
    [Google Scholar]
  77. Yu H. Liu J. Bu X. Ma Z. Yao Y. Li J. Zhang T. Song W. Xiao X. Sun Y. Xiong W. Shi J. Dai P. Xiang B. Duan H. Yan X. Wu F. Zhang W.C. Lin D. Hu H. Zhang H. Slack F.J. He H.H. Freeman G.J. Wei W. Zhang J. Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy. Cell Chem. Biol. 2024 31 4 776 791.e7 10.1016/j.chembiol.2023.09.001 37751743
    [Google Scholar]
  78. Song H. Song J. Cheng M. Zheng M. Wang T. Tian S. Flavell R.A. Zhu S. Li H.B. Ding C. Wei H. Sun R. Peng H. Tian Z. METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells. Nat. Commun. 2021 12 1 5522 5522 10.1038/s41467‑021‑25803‑0 34535671
    [Google Scholar]
  79. Xu L. Li K. Li J. Xu F. Liang S. Kong Y. Chen B. IL-18 serves as a main effector of CAF-derived METTL3 against immunosuppression of NSCLC via driving NF-κB pathway. Epigenetics 2023 18 1 2265625 2265625 10.1080/15592294.2023.2265625 37871286
    [Google Scholar]
  80. Bougras-Cartron G. Nadaradjane A. Joalland M.P. Lalier-Bretaudeau L. Raimbourg J. Cartron P.F. Adenosine methylation level of miR-125a-5p promotes anti-PD-1 therapy escape through the regulation of IGSF11/VSIG3 expression. Cancers 2023 15 12 3188 10.3390/cancers15123188 37370798
    [Google Scholar]
  81. Wu Y. Song Y. Wang R. Wang T. Molecular mechanisms of tumor resistance to radiotherapy. Mol. Cancer 2023 22 1 96 96 10.1186/s12943‑023‑01801‑2 37322433
    [Google Scholar]
  82. Sun X. Bai C. Li H. Xie D. Chen S. Han Y. Luo J. Li Y. Ye Y. Jia J. Huang X. Guan H. Long D. Huang R. Gao S. Zhou P.K. PARP1 modulates METTL3 promoter chromatin accessibility and associated LPAR5 RNA m6A methylation to control cancer cell radiosensitivity. Mol. Ther. 2023 31 9 2633 2650 10.1016/j.ymthe.2023.07.018 37482682
    [Google Scholar]
  83. Xu X. Zhang P. Huang Y. Shi W. Mao J. Ma N. Kong L. Guo L. Liu J. Chen J. Lu R. METTL3 ‐mediated m6A mRNA contributes to the resistance of carbon‐ion radiotherapy in non‐small‐cell lung cancer. Cancer Sci. 2023 114 1 105 114 10.1111/cas.15590 36114749
    [Google Scholar]
  84. Bedi R.K. Huang D. Eberle S.A. Wiedmer L. Śledź P. Caflisch A. Small‐molecule inhibitors of METTL3, the major human epitranscriptomic writer. ChemMedChem 2020 15 9 744 748 10.1002/cmdc.202000011 32159918
    [Google Scholar]
  85. Du Y. Yuan Y. Xu L. Zhao F. Wang W. Xu Y. Tian X. Discovery of METTL3 small molecule inhibitors by virtual screening of natural products. Front. Pharmacol. 2022 13 878135 878135 10.3389/fphar.2022.878135 35571106
    [Google Scholar]
  86. Lee J.H. Kim S. Jin M.S. Kim Y.C. Discovery of substituted indole derivatives as allosteric inhibitors of m6 A-RNA methyltransferase, METTL3-14 complex. Drug Dev. Res. 2022 83 3 783 799 35040501
    [Google Scholar]
  87. Moroz-Omori E.V. Huang D. Kumar Bedi R. Cheriyamkunnel S.J. Bochenkova E. Dolbois A. Rzeczkowski M.D. Li Y. Wiedmer L. Caflisch A. METTL3 inhibitors for epitranscriptomic modulation of cellular processes. ChemMedChem 2021 16 19 3035 3043 10.1002/cmdc.202100291 34237194
    [Google Scholar]
  88. Yanagi Y. Watanabe T. Hara Y. Sato Y. Kimura H. Murata T. EBV exploits RNA m(6)A modification to promote cell survival and progeny virus production during lytic cycle. Front. Microbiol. 2022 13 870816 10.3389/fmicb.2022.870816 35783391
    [Google Scholar]
  89. Li Z. Feng Y. Han H. Jiang X. Chen W. Ma X. Mei Y. Yuan D. Zhang D. Shi J. A stapled peptide inhibitor targeting the binding interface of N6‐adenosine‐methyltransferase subunits METTL3 and METTL14 for cancer therapy. Angew. Chem. Int. Ed. 2024 63 24 e202402611 10.1002/anie.202402611 38607929
    [Google Scholar]
  90. Dolbois A. Bedi R.K. Bochenkova E. Müller A. Moroz-Omori E.V. Huang D. Caflisch A. 1,4,9-Triazaspiro[5.5]undecan-2-one derivatives as potent and selective METTL3 inhibitors. J. Med. Chem. 2021 64 17 12738 12760 10.1021/acs.jmedchem.1c00773 34431664
    [Google Scholar]
  91. Du W. Huang Y. Chen X. Deng Y. Sun Y. Yang H. Shi Q. Wu F. Liu G. Huang H. Discovery of a PROTAC degrader for METTL3-METTL14 complex. Cell Chem Biol 2024 31 1 177 183 10.1016/j.chembiol.2023.12.009
    [Google Scholar]
  92. Yankova E. Blackaby W. Albertella M. Rak J. De Braekeleer E. Tsagkogeorga G. Pilka E.S. Aspris D. Leggate D. Hendrick A.G. Webster N.A. Andrews B. Fosbeary R. Guest P. Irigoyen N. Eleftheriou M. Gozdecka M. Dias J.M.L. Bannister A.J. Vick B. Jeremias I. Vassiliou G.S. Rausch O. Tzelepis K. Kouzarides T. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature 2021 593 7860 597 601 10.1038/s41586‑021‑03536‑w 33902106
    [Google Scholar]
  93. Zhang Z.W. Teng X. Zhao F. Ma C. Zhang J. Xiao L.F. Wang Y. Chang M. Tian Y. Li C. Zhang Z. Song S. Tong W.M. Liu P. Niu Y. METTL3 regulates m6A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma. Cell Rep. 2022 41 4 111530 10.1016/j.celrep.2022.111530 36288719
    [Google Scholar]
  94. An X. Wu W. Yang L. Dong J. Liu B. Guo J. Chen J. Guo B. Cao W. Jiang Q. ZBTB7C m6A modification incurred by METTL3 aberration promotes osteosarcoma progression. Transl. Res. 2023 259 62 71 10.1016/j.trsl.2023.04.005 37121538
    [Google Scholar]
  95. Chen H. Pan Y. Zhou Q. Liang C. Wong C.C. Zhou Y. Huang D. Liu W. Zhai J. Gou H. Su H. Zhang X. Xu H. Wang Y. Kang W. Kei Wu W.K. Yu J. METTL3 inhibits antitumor immunity by targeting m6A-BHLHE41-CXCL1/CXCR2 axis to promote colorectal cancer. Gastroenterology 2022 163 4 891 907 10.1053/j.gastro.2022.06.024 35700773
    [Google Scholar]
  96. Pomaville M. Chennakesavalu M. Wang P. Jiang Z. Sun H.L. Ren P. Borchert R. Gupta V. Ye C. Ge R. Zhu Z. Brodnik M. Zhong Y. Moore K. Salwen H. George R.E. Krajewska M. Chlenski A. Applebaum M.A. He C. Cohn S.L. Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation. Cell Rep. 2024 43 5 114165 114165 10.1016/j.celrep.2024.114165 38691450
    [Google Scholar]
  97. Liu Q. Qi J. Li W. Tian X. Zhang J. Liu F. Lu X. Zang H. Liu C. Ma C. Yu Y. Jiang S. Therapeutic effect and transcriptome-methylome characteristics of METTL3 inhibition in liver hepatocellular carcinoma. Cancer Cell Int. 2023 23 1 298 298 10.1186/s12935‑023‑03096‑1 38012755
    [Google Scholar]
  98. Wang J. Fan P. Shen P. Fan C. Zhao P. Yao shen Dong K. Ling R. Chen S. Zhang J. XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer. Cancer Lett. 2024 596 216846 10.1016/j.canlet.2024.216846 38582397
    [Google Scholar]
  99. Gao J. Fang Y. Chen J. Tang Z. Tian M. Jiang X. Tao C. Huang R. Zhu G. Qu W. Wu X. Zhou J. Fan J. Liu W. Shi Y. Methyltransferase like 3 inhibition limits intrahepatic cholangiocarcinoma metabolic reprogramming and potentiates the efficacy of chemotherapy. Oncogene 2023 42 33 2507 2520 10.1038/s41388‑023‑02760‑0 37420030
    [Google Scholar]
  100. Ke J. Zhang C. Wang L. Xie F. Wu H.Y. Li T. Bian C.W. Wu R.L. Lipopolysaccharide promotes cancer cell migration and invasion through METTL3/PI3K/AKT signaling in human cholangiocarcinoma. Heliyon 2024 10 8 e29683 e29683 10.1016/j.heliyon.2024.e29683 38681552
    [Google Scholar]
  101. Hao S. Sun H. Sun H. Zhang B. Ji K. Liu P. Nie F. Han W. STM2457 inhibits the invasion and metastasis of pancreatic cancer by down-regulating BRAF-activated noncoding RNA N6-Methyladenosine modification. Curr. Issues Mol. Biol. 2023 45 11 8852 8863 10.3390/cimb45110555 37998732
    [Google Scholar]
  102. Xuan Y.F. Lu S. Ou Y.J. Bao X.B. Huan X.J. Song S.S. Miao Z.H. Wang Y.Q. The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity. Biochem. Biophys. Res. Commun. 2024 716 150011 10.1016/j.bbrc.2024.150011 38704890
    [Google Scholar]
  103. Yang Y. Zhang Y. Chen G. Sun B. Luo F. Gao Y. Feng H. Li Y. KAP1 stabilizes MYCN mRNA and promotes neuroblastoma tumorigenicity by protecting the RNA m6A reader YTHDC1 protein degradation. J. Exp. Clin. Cancer Res. 2024 43 1 141 141 10.1186/s13046‑024‑03040‑9 38745192
    [Google Scholar]
  104. Ouyang D. Hong T. Fu M. Li Y. Zeng L. Chen Q. He H. Wen Y. Cheng Y. Zhou M. Zou Q. Yi W. METTL3 depletion contributes to tumour progression and drug resistance via N6 methyladenosine-dependent mechanism in HR+HER2—breast cancer. Breast Cancer Res. 2023 25 1 19 10.1186/s13058‑022‑01598‑w 36765397
    [Google Scholar]
/content/journals/cctr/10.2174/0115733947364895250307042821
Loading
Exploring the Function of METTL3 in Lung Cancer: Understanding Drug Resistance and Exploring Innovative Therapeutic Approaches
Bentham Science Publishers ; https://doi.org/10.2174/0115733947364895250307042821
/content/journals/cctr/10.2174/0115733947364895250307042821
/content/journals/cctr/10.2174/0115733947364895250307042821
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: chemotherapy resistance ; Lung cancer ; METTL3 ; m6A modification ; drug resistance

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test