Exploration of Targeted Anti-tumor Therapy

Table 1. MGMT-targeted strategies in cancer

Strategy	Mode of action	Remarks/Examples
Direct MGMT inhibitors	Irreversibly binds and inactivates MGMT to deplete its activity	O⁶-Benzylguanine (O⁶-BG); enhances TMZ efficacy but may cause myelotoxicity
Epigenetic silencing	Induce MGMT promoter methylation or alter chromatin to reduce transcription	Use of DNMT inhibitors (decitabine) or HDAC inhibitors (vorinostat)
RNA-based approaches	Use siRNA, shRNA, or ASOs to degrade MGMT mRNA or block translation	Experimental use of MGMT siRNA or antisense oligonucleotides like ALZ003
CRISPR/Cas9-mediated knockout	Gene editing to remove the MGMT gene function	Preclinical models to study TMZ sensitization
Targeted drug delivery	Deliver MGMT inhibitors selectively to tumor cells to minimize toxicity	Nanoparticles or liposomes loaded with O⁶-BG or MGMT siRNA

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DNMT: DNA methyltransferase; MGMT: O⁶-methylguanine-DNA methyltransferase; TMZ: temozolomide; HADC: histone deacetylase

Declarations

Author contributions

SS: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. RN: Writing—review & editing. MB: Writing—review & editing. ASK: Conceptualization, Validation, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

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Consent to participate

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Consent to publication

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Availability of data and materials

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Funding

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Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Kaina B, Christmann M, Naumann S, Roos WP. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst). 2007;6:1079–99. [DOI] [PubMed]

Bai P, Fan T, Sun G, Wang X, Zhao L, Zhong R. The dual role of DNA repair protein MGMT in cancer prevention and treatment. DNA Repair (Amst). 2023;123:103449. [DOI] [PubMed]

Fan CH, Liu WL, Cao H, Wen C, Chen L, Jiang G. O6-methylguanine DNA methyltransferase as a promising target for the treatment of temozolomide-resistant gliomas. Cell Death Dis. 2013;4:e876. [DOI] [PubMed] [PMC]

Verbeek B, Southgate TD, Gilham DE, Margison GP. O6-Methylguanine-DNA methyltransferase inactivation and chemotherapy. Br Med Bull. 2008;85:17–33. [DOI] [PubMed]

Yu W, Zhang L, Wei Q, Shao A. O⁶-Methylguanine-DNA Methyltransferase (MGMT): Challenges and New Opportunities in Glioma Chemotherapy. Front Oncol. 2020;9:1547. [DOI] [PubMed] [PMC]

Gupta MK, Kushwah AS, Singh R, Srivastava K, Banerjee M. Genetic and epigenetic alterations in MGMT gene and correlation with concomitant chemoradiotherapy (CRT) in cervical cancer. J Cancer Res Clin Oncol. 2023;149:15159–70. [DOI] [PubMed] [PMC]

Pegg AE. Repair of O(6)-alkylguanine by alkyltransferases. Mutat Res. 2000;462:83–100. [DOI] [PubMed]

Mostofa A, Punganuru SR, Madala HR, Srivenugopal KS. S-phase Specific Downregulation of Human O⁶-Methylguanine DNA Methyltransferase (MGMT) and its Serendipitous Interactions with PCNA and p21^cip1Proteins in Glioma Cells. Neoplasia. 2018;20:305–23. [DOI] [PubMed] [PMC]

Abdelhady R, Senthong P, Eyers CE, Reamtong O, Cowley E, Cannizzaro L, et al. Mass Spectrometric Analysis of the Active Site Tryptic Peptide of Recombinant O⁶-Methylguanine-DNA Methyltransferase Following Incubation with Human Colorectal DNA Reveals the Presence of an O⁶-Alkylguanine Adductome. Chem Res Toxicol. 2023;36:1921–9. [DOI] [PubMed] [PMC]

10.

Wickström M, Dyberg C, Milosevic J, Einvik C, Calero R, Sveinbjörnsson B, et al. Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance. Nat Commun. 2015;6:8904. [DOI] [PubMed] [PMC]

11.

Leng S, Wu G, Collins LB, Thomas CL, Tellez CS, Jauregui AR, et al. Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung. Cancer Res. 2015;75:3108–17. [DOI] [PubMed] [PMC]

12.

Cankovic M. Laboratory Testing for Prognostic and Predictive Markers in Gliomas. In: Lichtor T, editor. Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors. Rijeka: IntechOpen; 2013.

13.

Lv Y, Jia C, Jiang A, Zhang H, Wang Y, Liu F, et al. Analysis of Association Between MGMT and p53 Gene Single Nucleotide Polymorphisms and Laryngeal Cancer. Anticancer Res. 2017;37:4399–403. [DOI] [PubMed]

14.

Ahmed Aglan S, Mohamad Zaki A, Sobhy El Sedfy A, Gaber El-Sheredy H, Hussein Elgaddar O. O6-Methylguanine-DNA Methyltransferase and ATP-Binding Cassette Membrane Transporter G2 Promotor Methylation: Can Predict the Response to Chemotherapy in Advanced Breast Cancer? Rep Biochem Mol Biol. 2022;11:20–9. [DOI] [PubMed] [PMC]

15.

Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000;343:1350–4. [DOI] [PubMed]

16.

Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003. [DOI] [PubMed]

17.

Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21:5427–40. [DOI] [PubMed]

18.

Nakagawachi T, Soejima H, Urano T, Zhao W, Higashimoto K, Satoh Y, et al. Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer. Oncogene. 2003;22:8835–44. [DOI] [PubMed]

19.

Srivenugopal KS, Shou J, Mullapudi SR, Lang FF Jr, Rao JS, Ali-Osman F. Enforced expression of wild-type p53 curtails the transcription of the O(6)-methylguanine-DNA methyltransferase gene in human tumor cells and enhances their sensitivity to alkylating agents. Clin Cancer Res. 2001;7:1398–409. [PubMed]

20.

Sabharwal A, Middleton MR. Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy. Curr Opin Pharmacol. 2006;6:355–63. [DOI] [PubMed]

21.

Geng X, Zhang Y, Lin X, Zeng Z, Hu J, Hao L, et al. Exosomal circWDR62 promotes temozolomide resistance and malignant progression through regulation of the miR-370-3p/MGMT axis in glioma. Cell Death Dis. 2022;13:596. [DOI] [PubMed] [PMC]

22.

Chen Z, Xiang B, Qi L, Zhu S, Li L. miR-221-3p promotes hepatocellular carcinogenesis by downregulating O6-methylguanine-DNA methyltransferase. Cancer Biol Ther. 2020;21:915–26. [DOI] [PubMed] [PMC]

23.

Kushihara Y, Tanaka S, Kobayashi Y, Nagaoka K, Kikuchi M, Nejo T, et al. Glioblastoma with high O6-methyl-guanine DNA methyltransferase expression are more immunologically active than tumors with low MGMT expression. Front Immunol. 2024;15:1328375. [DOI] [PubMed] [PMC]

24.

Li Q, Guo J, Wang W, Wang D. Relationship between MGMT gene expression and treatment effectiveness and prognosis in glioma. Oncol Lett. 2017;14:229–33. [DOI] [PubMed] [PMC]

25.

Cabrini G, Fabbri E, Lo Nigro C, Dechecchi MC, Gambari R. Regulation of expression of O6-methylguanine-DNA methyltransferase and the treatment of glioblastoma (Review). Int J Oncol. 2015;47:417–28. [DOI] [PubMed] [PMC]

26.

Jakob J, Hille M, Sauer C, Ströbel P, Wenz F, Hohenberger P. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a rare event in soft tissue sarcoma. Radiat Oncol. 2012;7:180. [DOI] [PubMed] [PMC]

27.

Chen X, Zhang M, Gan H, Wang H, Lee JH, Fang D, et al. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nat Commun. 2018;9:2949. [DOI] [PubMed] [PMC]

28.

Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31:4085–91. [DOI] [PubMed] [PMC]

29.

Shen X, Yang Y, Yang Z, Liu N, Qi X, Xu H, et al. Evaluation of 06-methylguanine-DNA methyltransferase expression in children and adolescent pituitary adenoma. Research Square [Preprint]. 2020 [cited 2025 Jul 27]. Available from: https://www.researchsquare.com/article/rs-54592/v1

30.

Chahal M, Xu Y, Lesniak D, Graham K, Famulski K, Christensen JG, et al. MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro Oncol. 2010;12:822–33. [DOI] [PubMed] [PMC]

31.

Zhao L, Zhang J, Xuan S, Liu Z, Wang Y, Zhao P. Molecular and clinicopathological characterization of a prognostic immune gene signature associated with MGMT methylation in glioblastoma. bioRxiv [Preprint]. 2020 [cited 2025 Jul 27]. Available from: https://www.biorxiv.org/content/early/2020/08/26/2020.07.16.206318

32.

Fishman H, Monin R, Dor-On E, Kinzel A, Haber A, Giladi M, et al. Tumor Treating Fields (TTFields) increase the effectiveness of temozolomide and lomustine in glioblastoma cell lines. J Neurooncol. 2023;163:83–94. [DOI] [PubMed] [PMC]

33.

Lamb KL, Liu Y, Ishiguro K, Kwon Y, Paquet N, Sartorelli AC, et al. Tumor-associated mutations in O⁶-methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality. Mol Carcinog. 2014;53:201–10. [DOI] [PubMed] [PMC]

34.

Tanaka H, Sasayama T, Nishihara M, Arai A, Kawamura A, Kanomata N, et al. Brain metastasis of undifferentiated sarcoma and response to temozolomide treatment. Case report. Neurol Med Chir (Tokyo). 2010;50:689–93. [DOI] [PubMed]

35.

Ren X, Li H, Song X, Wu Y, Liu Y. 5-Azacytidine treatment induces demethylation of DAPK1 and MGMT genes and inhibits growth in canine mammary gland tumor cells. Onco Targets Ther. 2018;11:2805–13. [DOI] [PubMed] [PMC]

36.

Villalva C, Cortes U, Wager M, Tourani JM, Rivet P, Marquant C, et al. O6-Methylguanine-methyltransferase (MGMT) promoter methylation status in glioma stem-like cells is correlated to temozolomide sensitivity under differentiation-promoting conditions. Int J Mol Sci. 2012;13:6983–94. [DOI] [PubMed] [PMC]

37.

Kushwah AS, Gupta MK, Singh R, Banerjee M. Cytokine gene variants and treatment outcome of cisplatin-based concomitant chemoradiotherapy in cervical cancer. Br J Biomed Sci. 2020;77:81–6. [DOI] [PubMed]

38.

Kushwah AS, Gupta MK, Srivastava K, Banerjee M. Cytokine Gene Variants as Risk Predictors and Prognostic Biomarkers for Cervix Cancer: A Revisit. Curr Cancer Ther Rev. 2025;21:1–11. [DOI]

39.

Kaushik M, Chandra Joshi R, Kushwah AS, Gupta MK, Banerjee M, Burget R, et al. Cytokine gene variants and socio-demographic characteristics as predictors of cervical cancer: A machine learning approach. Comput Biol Med. 2021;134:104559. [DOI] [PubMed]

40.

Zhang J, Stevens MF, Laughton CA, Madhusudan S, Bradshaw TD. Acquired resistance to temozolomide in glioma cell lines: molecular mechanisms and potential translational applications. Oncology. 2010;78:103–14. [DOI] [PubMed]

41.

Chen L, Wen A. Unveiling the role of O(6)-methylguanine-DNA methyltransferase in cancer therapy: insights into alkylators, pharmacogenomics, and others. Front Oncol. 2024;14:1424797. [DOI] [PubMed] [PMC]

42.

Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, et al.; German Glioma Network. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer. 2011;129:659–70. [DOI] [PubMed]

43.

Persano L, Pistollato F, Rampazzo E, Della Puppa A, Abbadi S, Frasson C, et al. BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression. Cell Death Dis. 2012;3:e412. [DOI] [PubMed] [PMC]

44.

Hassel JC, Sucker A, Edler L, Kurzen H, Moll I, Stresemann C, et al. MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome. Br J Cancer. 2010;103:820–6. [DOI] [PubMed] [PMC]

45.

Shi J, Zhang P, Dong X, Yuan J, Li Y, Li S, et al. METTL3 knockdown promotes temozolomide sensitivity of glioma stem cells via decreasing MGMT and APNG mRNA stability. Cell Death Discov. 2023;9:22. [DOI] [PubMed] [PMC]

46.

Sak M, Williams BJ, Hey AJ, Sharma M, Schier L, Wilson MJ, et al. O⁶-methylguanine DNA methyltransferase (MGMT) expression in U1242 glioblastoma cells enhances in vitro clonogenicity, tumor implantation in vivo, and sensitivity to alisertib-carboplatin combination treatment. Front Cell Neurosci. 2025;19:1552015. [DOI] [PubMed] [PMC]

47.

Kirstein A, Schilling D, Combs SE, Schmid TE. Lomeguatrib Increases the Radiosensitivity of MGMT Unmethylated Human Glioblastoma Multiforme Cell Lines. Int J Mol Sci. 2021;22:6781. [DOI] [PubMed] [PMC]

48.

Uno M, Oba-Shinjo SM, Camargo AA, Moura RP, Aguiar PH, Cabrera HN, et al. Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma. Clinics (Sao Paulo). 2011;66:1747–55. [DOI] [PubMed] [PMC]

49.

Köritzer J, Boxhammer V, Schäfer A, Shimizu T, Klämpfl TG, Li YF, et al. Restoration of sensitivity in chemo-resistant glioma cells by cold atmospheric plasma. PLoS One. 2013;8:e64498. [DOI] [PubMed] [PMC]

50.

Kitange GJ, Mladek AC, Carlson BL, Schroeder MA, Pokorny JL, Cen L, et al. Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts. Clin Cancer Res. 2012;18:4070–9. [DOI] [PubMed] [PMC]

51.

inslow CJ, Mercurio A, Kumar P, Rae AI, Siegelin MD, Grinband J, et al. Association of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy. JAMA Oncol. 2023;9:919–27. [DOI] [PubMed] [PMC]

52.

Happold C, Stojcheva N, Silginer M, Weiss T, Roth P, Reifenberger G, et al. Transcriptional control of O⁶-methylguanine DNA methyltransferase expression and temozolomide resistance in glioblastoma. J Neurochem. 2018;144:780–90. [DOI] [PubMed]

53.

Alassiri AH, Alkhaibary A, Al-Sarheed S, Alsufani F, Alharbi M, Alkhani A, et al. O⁶-methylguanine-DNA methyltransferase promoter methylation and isocitrate dehydrogenase mutation as prognostic factors in a cohort of Saudi patients with glioblastoma. Ann Saudi Med. 2019;39:410–6. [DOI] [PubMed] [PMC]

54.

Blough MD, Zlatescu MC, Cairncross JG. O6-methylguanine-DNA methyltransferase regulation by p53 in astrocytic cells. Cancer Res. 2007;67:580–4. [DOI] [PubMed]

55.

Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27:5743–50. [DOI] [PubMed]

56.

Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, et al. Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer. 2009;101:124–31. [DOI] [PubMed] [PMC]

57.

Oberstadt MC, Bien-Möller S, Weitmann K, Herzog S, Hentschel K, Rimmbach C, et al. Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme. BMC Cancer. 2013;13:617. [DOI] [PubMed] [PMC]

58.

Ishii D, Natsume A, Wakabayashi T, Hatano H, Asano Y, Takeuchi H, et al. Efficacy of temozolomide is correlated with 1p loss and methylation of the deoxyribonucleic acid repair gene MGMT in malignant gliomas. Neurol Med Chir (Tokyo). 2007;47:341–50. [DOI] [PubMed]

59.

Kurdi M, Shafique Butt N, Baeesa S, Alghamdi B, Maghrabi Y, Bardeesi A, et al. The Impact of IDH1 Mutation and MGMT Promoter Methylation on Recurrence-Free Interval in Glioblastoma Patients Treated With Radiotherapy and Chemotherapeutic Agents. Pathol Oncol Res. 2021;27:1609778. [DOI] [PubMed] [PMC]

60.

Chehade G, El Hajj N, Aittaleb M, Alkailani MI, Bejaoui Y, Mahdi A, et al. DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma. Front Oncol. 2024;14:1359652. [DOI] [PubMed] [PMC]

61.

Baguley BC, Joseph WR, Murray PM, Stowell KM, Leung EY, Marshall ES. Sensitivity to temozolomide of cell lines derived from brain tumours and melanomas: relationship to MGMT gene expression. bioRxiv [Preprint]. 2024 [cited 2025 Jul 27]. Available from: https://www.biorxiv.org/content/early/2024/12/05/2024.11.30.626133

62.

Håvik AB, Brandal P, Honne H, Dahlback HS, Scheie D, Hektoen M, et al. MGMT promoter methylation in gliomas-assessment by pyrosequencing and quantitative methylation-specific PCR. J Transl Med. 2012;10:36. [DOI] [PubMed] [PMC]

63.

Zawlik I, Vaccarella S, Kita D, Mittelbronn M, Franceschi S, Ohgaki H. Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology. 2009;32:21–9. [DOI] [PubMed]

64.

Wu S, Li X, Gao F, de Groot JF, Koul D, Yung WKA. PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma. Neuro Oncol. 2021;23:920–31. [DOI] [PubMed] [PMC]

65.

Hwang K, Lee JH, Kim SH, Go KO, Ji SY, Han JH, et al. The Combination PARP Inhibitor Olaparib With Temozolomide in an Experimental Glioblastoma Model. In Vivo. 2021;35:2015–23. [DOI] [PubMed] [PMC]

66.

Kim H, Xu H, George E, Hallberg D, Kumar S, Jagannathan V, et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun. 2020;11:3726. [DOI] [PubMed] [PMC]

67.

Kim MJ, Lee SW, Park SB, Lee YJ, Kim YM. Combination of olaparib and savolitinib overcomes olaparib-resistance in epithelial ovarian cancer models. Research Square [Preprint]. 2023 [cited 2025 Jul 27]. Available from: https://www.researchsquare.com/article/rs-2540583/v1

68.

Dorado García H, Pusch F, Bei Y, von Stebut J, Ibáñez G, Guillan K, et al. Therapeutic targeting of ATR in alveolar rhabdomyosarcoma. Nat Commun. 2022;13:4297. [DOI] [PubMed] [PMC]

69.

Bisht P, Prasad SR, Choudhary K, Pandey R, Aishwarya D, Aravind V, et al. Naringin and temozolomide combination suppressed the growth of glioblastoma cells by promoting cell apoptosis: network pharmacology, in-vitro assays and metabolomics based study. Front Pharmacol. 2024;15:1431085. [DOI] [PubMed] [PMC]

70.

Wikiniyadhanee R, Lerksuthirat T, Stitchantrakul W, Chitphuk S, Takeda S, Dejsuphong D. ATR Inhibitor Synergizes PARP Inhibitor Cytotoxicity in Homologous Recombination Repair Deficiency TK6 Cell Lines. Biomed Res Int. 2023;2023:7891753. [DOI] [PubMed] [PMC]

71.

Lerksuthirat T, Prasopporn S, Wikiniyadhanee R, Chitphuk S, Stitchantrakul W, Owneium P, et al. DNA damage response mutations enhance the antitumor efficacy of ATR and PARP inhibitors in cholangiocarcinoma cell lines. Oncol Lett. 2025;29:128. [DOI] [PubMed] [PMC]

72.

Leong VWS, Khan S, Sharma P, Wu S, Thomas RR, Li X, et al. MGMT function determines the differential response of ATR inhibitors with DNA-damaging agents in glioma stem cells for GBM therapy. Neurooncol Adv. 2023;6:vdad165. [DOI] [PubMed] [PMC]

73.

Brandner S, McAleenan A, Kelly C, Spiga F, Cheng HY, Dawson S, et al. MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review. Neuro Oncol. 2021;23:1457–69. [DOI] [PubMed] [PMC]

74.

Rajanathadurai J, Perumal E, Sindya J. Advances in targeting cancer epigenetics using CRISPR-dCas9 technology: A comprehensive review and future prospects. Funct Integr Genomics. 2024;24:164. [DOI] [PubMed]

75.

Vatapalli R, Rossi AP, Chan HM, Zhang J. Cancer epigenetic therapy: recent advances, challenges, and emerging opportunities. Epigenomics. 2025;17:59–74. [DOI] [PubMed] [PMC]

76.

Di Carlo E, Sorrentino C. State of the art CRISPR-based strategies for cancer diagnostics and treatment. Biomark Res. 2024;12:156. [DOI] [PubMed] [PMC]

77.

Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell. 2016;164:550–63. [DOI] [PubMed] [PMC]

78.

GLASS Consortium. Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium. Neuro Oncol. 2018;20:873–84. [DOI] [PubMed] [PMC]

79.

Majd N, Yeboa D, Wang S, Weathers SPS, Yuan Y, Al Anssari H, et al. Phase I clinical trial of peposertib plus radiation in adults with newly diagnosed MGMT-unmethylated glioblastoma. J Clin Oncol. 2024;42:2076.

80.

Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al.; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77. [DOI] [PubMed] [PMC]

81.

Alnahhas I, Alsawas M, Rayi A, Palmer JD, Raval R, Ong S, et al. Characterizing benefit from temozolomide in MGMT promoter unmethylated and methylated glioblastoma: a systematic review and meta-analysis. Neurooncol Adv. 2020;2:vdaa082. [DOI] [PubMed] [PMC]

82.

Pandith AA, Qasim I, Zahoor W, Shah P, Bhat AR, Sanadhya D, et al. Concordant association validates MGMT methylation and protein expression as favorable prognostic factors in glioma patients on alkylating chemotherapy (Temozolomide). Sci Rep. 2018;8:6704. [DOI] [PubMed] [PMC]

83.

Minoo P. Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT. Front Oncol. 2013;3:266. [DOI] [PubMed] [PMC]

84.

Hoang PH, Landi MT. DNA Methylation in Lung Cancer: Mechanisms and Associations with Histological Subtypes, Molecular Alterations, and Major Epidemiological Factors. Cancers (Basel). 2022;14:961. [DOI] [PubMed] [PMC]

85.

Chen R, Zheng Y, Zhuo L, Wang S. Association between MGMT Promoter Methylation and Risk of Breast and Gynecologic Cancers: A Systematic Review and Meta-Analysis. Sci Rep. 2017;7:12783. [DOI] [PubMed] [PMC]

86.

Yagi K, Ono H, Kudo A, Kinowaki Y, Asano D, Watanabe S, et al. Inactivation of MGMT is Associated With the Efficacy of Streptozocin and High-grade Pancreatic Neuroendocrine Neoplasms. Research Square [Preprint]. 2023 [cited 2025 Jul 27]. Available from: https://www.researchsquare.com/article/rs-2161835/v1

87.

Salehi F, Scheithauer BW, Kros JM, Lau Q, Fealey M, Erickson D, et al. MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas. J Neurooncol. 2011;104:647–57. [DOI] [PubMed]

88.

Sun P, Fan DJ, Fan T, Li X, Qi XL, Zhao XG, et al. A Prospective Clinical Study on MGMT Protein Expression and the Effect of Gene Promoter Methylation on Sensitivity to Chemotherapeutics in Spinal Glioma. J Inflamm Res. 2021;14:4777–84. [DOI] [PubMed] [PMC]

89.

Cui Q, Jiang W, Guo J, Liu C, Li D, Wang X, et al. Relationship between hypermethylated MGMT gene and osteosarcoma necrosis rate after chemotherapy. Pathol Oncol Res. 2011;17:587–91. [DOI] [PubMed]

90.

Su Y, Liu R, Sheng J, Liu H, Wang Y, Pan E, et al. Malignant progression in O6-methylguanine-DNA methyltransferase-deficient esophageal cancer cells is associated with Ezrin protein. DNA Cell Biol. 2012;31:856–66. [DOI] [PubMed]

91.

Schraml P, von Teichman A, Mihic-Probst D, Simcock M, Ochsenbein A, Dummer R, et al. Predictive value of the MGMT promoter methylation status in metastatic melanoma patients receiving first-line temozolomide plus bevacizumab in the trial SAKK 50/07. Oncol Rep. 2012;28:654–8. [DOI] [PubMed]

92.

Roh HJ, Suh DS, Choi KU, Yoo HJ, Joo WD, Yoon MS. Inactivation of O⁶-methyguanine-DNA methyltransferase by promoter hypermethylation: association of epithelial ovarian carcinogenesis in specific histological types. J Obstet Gynaecol Res. 2011;37:851–60. [DOI] [PubMed]

93.

Giaginis C, Michailidi C, Stolakis V, Alexandrou P, Tsourouflis G, Klijanienko J, et al. Expression of DNA repair proteins MSH2, MLH1 and MGMT in human benign and malignant thyroid lesions: an immunohistochemical study. Med Sci Monit. 2011;17:BR81–90. [DOI] [PubMed] [PMC]

94.

Clark SJ, Lee HJ, Smallwood SA, Kelsey G, Reik W. Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity. Genome Biol. 2016;17:72. [DOI] [PubMed] [PMC]

95.

Topol EJ. High-performance medicine: the convergence of human and artificial intelligence. Nat Med. 2019;25:44–56. [DOI] [PubMed]