Temozolomide resistance in glioblastoma

Temozolomide resistance in glioblastoma

Temozolomide resistance is considered to be one of the major reasons responsible for glioblastoma treatment failure.

TMZ is currently the only mono-chemotherapeutic agent for newly-diagnosed high-grade glioma patients and acquired resistance inevitably occurs in the majority of such patients, further limiting treatment options. Therefore, there is an urgent need to better understand the underlying mechanisms involved in TMZ resistance, a critical step to developing effective, targeted treatments. An emerging body of evidence suggests the intimate involvement of a novel class of nucleic acid, microRNA (miRNA), in tumorigenesis and disease progression for a number of human malignancies, including primary brain tumours. miRNA are short, single-stranded, non-coding RNA (∼22 nucleotides) that function as post-transcriptional regulators of gene expression 1).

At least 50% of TMZ treated patients do not respond to TMZ. This is due primarily to the over-expression of O6-methylguanine methyltransferase (MGMT) and/or lack of a DNA repair pathway in GBM cells. Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics. However, the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared 2)


Many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathwaysautophagyepigenetic modificationsmicroRNAs, and extracellular vesicle production 3).


To date, aberrations in O6-methylguanine-DNA methyltransferase are the clear factor that determines drug susceptibility. Alterations of the other DNA damage repair genes such as DNA mismatch repair genes are also known to affect the drug effect. Together these genes have roles in the innate resistance, but are not sufficient for explaining the mechanism leading to acquired resistance. Recent identification of specific cellular subsets with features of stem-like cells may have role in this process. The glioma stem-like cells are known for its superior ability in withstanding the drug-induced cytotoxicity, and giving the chance to repopulate the tumor. The mechanism is complicated to administrate cellular protection, such as the enhancing ability against reactive oxygen species and altering energy metabolism, the important steps to survive 4).


Rabé et al. performed a longitudinal study, using a combination of mathematical models, RNA sequencing, single cell analyses, functional and drug assays in a human glioma cell line (U251). After an initial response characterized by cell death induction, cells entered a transient state defined by slow growth, a distinct morphology and a shift of metabolism. Specific genes expression associated to this population revealed chromatin remodeling. Indeed, the histone deacetylase inhibitor trichostatin (TSA), specifically eliminated this population and thus prevented the appearance of fast growing TMZ-resistant cells. In conclusion, they identified in glioblastoma a population with tolerant-like features, which could constitute a therapeutic target 5)


Ferroptosis, which is a new type of cell death discovered in recent years, has been reported to play an important role in tumor drug resistance. A study reviews the relationship between ferroptosis and glioma TMZ resistance, and highlights the role of ferroptosis in glioma TMZ resistance. Finally, the investigators discussed the future orientation for ferroptosis in glioma TMZ resistance, in order to promote the clinical use of ferroptosis induction in glioma treatment 6).


CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance 7).


CXCL12/CXCR4 has been demonstrated to be involved in cell proliferationcell migrationcell invasionangiogenesis, and radioresistance in glioblastoma (GBM). However, its role in TMZ resistance in GBM is unknown. Wang et al. aimed to evaluate the role of CXCL12/CXCR4 in mediating the TMZ resistance to GBM cells and explore the underlying mechanisms. They found that the CXCL12/CXCR4 axis enhanced TMZ resistance in GBM cells. Further study showed that CXCL12/CXCR4 conferred TMZ resistance and promoted the migration and invasion of GBM cells by up-regulating FOXM1. This resistance was partially reversed by suppressing CXCL12/CXCR4 and FOXM1 silencing. This study revealed the vital role of CXCL12/CXCR4 in mediating the resistance of GBM cells to TMZ, and suggested that targeting CXCL12/CXCR4 axis may attenuate the resistance to TMZ in GBM 8).


The YTHDF2 expression in TMZ-resistant tissues and cells was detected. Kaplan-Meier analysis was employed to evaluate the prognostic value of YTHDF2 in GBM. Effect of YTHDF2 in TMZ resistance in GBM was explored via corresponding experiments. RNA sequence, FISH in conjugation with fluorescent immunostaining, RNA immunoprecipitation, dual-luciferase reporter gene and immunofluorescence were applied to investigate the mechanism of YTHDF2 that boosted TMZ resistance in GBM.

YTHDF2 was up-regulated in TMZ-resistant tissues and cells, and patients with high expression of YTHDF2 showed lower survival rate than the patients with low expression of YTHDF2. The elevated YTHDF2 expression boosted TMZ resistance in GBM cells, and the decreased YTHDF2 expression enhanced TMZ sensitivity in TMZ-resistant GBM cells. Mechanically, YTHDF2 bound to the N6-methyladenosine (m6A) sites in the 3’UTR of EPHB3 and TNFAIP3 to decrease the mRNA stability. YTHDF2 activated the PI3K/Akt and NF-κB signals through inhibiting expression of EPHB3 and TNFAIP3, and the inhibition of the two pathways attenuated YTHDF2-mediated TMZ resistance.

YTHDF2 enhanced TMZ resistance in GBM by activation of the PI3K/Akt and NF-κB signalling pathways via inhibition of EPHB3 and TNFAIP3 9).


1) 
Low SY, Ho YK, Too HP, Yap CT, Ng WH. MicroRNA as potential modulators in chemoresistant high-grade gliomas. J Clin Neurosci. 2013 Oct 6. pii: S0967-5868(13)00518-3. doi: 10.1016/j.jocn.2013.07.033. [Epub ahead of print] PubMed PMID: 24411131.
2) 
Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016 May 11;3(3):198-210. doi: 10.1016/j.gendis.2016.04.007. PMID: 30258889; PMCID: PMC6150109.
3) 
Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma – a comprehensive review. Cancer Drug Resist. 2021;4(1):17-43. doi: 10.20517/cdr.2020.79. Epub 2021 Mar 19. PMID: 34337348; PMCID: PMC8319838.
4) 
Chien CH, Hsueh WT, Chuang JY, Chang KY. Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma. J Biomed Sci. 2021 Mar 8;28(1):18. doi: 10.1186/s12929-021-00717-7. PMID: 33685470; PMCID: PMC7938520.
5) 
Rabé M, Dumont S, Álvarez-Arenas A, Janati H, Belmonte-Beitia J, Calvo GF, Thibault-Carpentier C, Séry Q, Chauvin C, Joalland N, Briand F, Blandin S, Scotet E, Pecqueur C, Clairambault J, Oliver L, Perez-Garcia V, Nadaradjane A, Cartron PF, Gratas C, Vallette FM. Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma. Cell Death Dis. 2020 Jan 6;11(1):19. doi: 10.1038/s41419-019-2200-2. PMID: 31907355; PMCID: PMC6944699.
6) 
Hu Z, Mi Y, Qian H, Guo N, Yan A, Zhang Y, Gao X. A Potential Mechanism of Temozolomide Resistance in Glioma-Ferroptosis. Front Oncol. 2020 Jun 23;10:897. doi: 10.3389/fonc.2020.00897. PMID: 32656078; PMCID: PMC7324762.
7) 
Ye X, Liu X, Gao M, Gong L, Tian F, Shen Y, Hu H, Sun G, Zou Y, Gong Y. CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription. Front Oncol. 2021 Apr 2;11:638802. doi: 10.3389/fonc.2021.638802. PMID: 33869025; PMCID: PMC8050354.
8) 
Wang S, Chen C, Li J, Xu X, Chen W, Li F. The CXCL12/CXCR4 axis confers temozolomide resistance to human glioblastoma cells via up-regulation of FOXM1. J Neurol Sci. 2020 Apr 14;414:116837. doi: 10.1016/j.jns.2020.116837. [Epub ahead of print] PubMed PMID: 32334273.
9) 
Chen Y, Wang YL, Qiu K, Cao YQ, Zhang FJ, Zhao HB, Liu XZ. YTHDF2 promotes temozolomide resistance in glioblastoma by activation of the Akt and NF-κB signalling pathways via inhibiting EPHB3 and TNFAIP3. Clin Transl Immunology. 2022 May 9;11(5):e1393. doi: 10.1002/cti2.1393. PMID: 35582627; PMCID: PMC9082891.

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