Acquired temozolomide resistance in MGMTlow gliomas is associated with regulation of homologous recombination repair by ROCK2

Zhang, Xin; Li, Tao; Yang, Mei; Du, Qianming; Wang, Rui; Fu, Bin; Tan, Yingying; Cao, Mingtao; Chen, Yaxin; Wang, Qing; Hu, Rong

doi:10.1038/s41419-022-04590-6

Cited by 13 publications

(16 citation statements)

References 47 publications

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“…1 ). Similar findings for an involvement of ATM in TMZ resistance of MGMT low expressing GBM cells have been also reported by others [ 51 – 53 ]. Thus, it needs to be further investigated if ATM inhibition may represent a sensitization approach for TMZ treatment of GBM with low MGMT expression.…”

Section: Resultssupporting

confidence: 91%

“…Similarly, the association of ATM expression with TMZ resistance in the context of MGMT low expressing GBM is an interesting novel finding disclosed by our study. Since similar findings were published before [ 51 – 53 ], and ATM inhibitors are currently undergoing clinical trialing in GBM (NCT03423628, NCT05182905), this observation should be further investigated in future. Nevertheless, there were also genes whose expression levels correlated with therapy resistance and whose functional involvement could not be validated.…”

Section: Discussionsupporting

confidence: 76%

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Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

et al. 2022

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Background Inherent resistance to radio/chemotherapy is one of the major reasons for early recurrence, treatment failure, and dismal prognosis of glioblastoma. Thus, the identification of resistance driving regulators as prognostic and/or predictive markers as well as potential vulnerabilities for combined modality treatment approaches is of pivotal importance. Methods We performed an integrative analysis of treatment resistance and DNA damage response regulator expression in a panel of human glioblastoma cell lines. mRNA expression levels of 38 DNA damage response regulators were analyzed by qRT-PCR. Inherent resistance to radiotherapy (single-shot and fractionated mode) and/or temozolomide treatment was assessed by clonogenic survival assays. Resistance scores were extracted by dimensionality reduction and subjected to correlation analyses with the mRNA expression data. Top-hit candidates with positive correlation coefficients were validated by pharmacological inhibition in clonogenic survival assays and DNA repair analyses via residual γH2AX/53BP1-foci staining. Results Inherent resistance to single-shot and similarly also to fractionated radiotherapy showed strong positive correlations with mRNA expression levels of known vulnerabilities of GBM, including PARP1, NBN, and BLM, as well as ATR and LIG4—two so far underestimated targets. Inhibition of ATR by AZD-6738 resulted in robust and dose-dependent radiosensitization of glioblastoma cells, whereas LIG4 inhibition by L189 had no noticeable impact. Resistance against temozolomide showed strong positive correlation with mRNA expression levels of MGMT as to be expected. Interestingly, it also correlated with mRNA expression levels of ATM, suggesting a potential role of ATM in the context of temozolomide resistance in glioblastoma cells. ATM inhibition exhibited slight sensitization effects towards temozolomide treatment in MGMT low expressing glioblastoma cells, thus encouraging further characterization. Conclusions Here, we describe a systematic approach integrating clonogenic survival data with mRNA expression data of DNA damage response regulators in human glioblastoma cell lines to identify markers of inherent therapy resistance and potential vulnerabilities for targeted sensitization. Our results provide proof-of-concept for the feasibility of this approach, including its limitations. We consider this strategy to be adaptable to other cancer entities as well as other molecular data qualities, and its upscaling potential in terms of model systems and observational data levels deserves further investigation.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 76%

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

et al. 2022

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“…The MGMT inhibitor O 6 -benzyl guanine upregulates the GB sensitivity to TMZ [ 5 , 11 , 12 ]. (3) Tumor DNA repair systems, such as the base excision repair (BER) and DNA strand break (DSB) repair, account for TMZ-induced alkylation and DSB failure [ 6 , 13 , 14 , 15 , 16 ]. In addition, within BER modulation, poly ADP ribose polymerase-1 (PARP-1) is essential for the recruitment of BER proteins and consequent DNA repair [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Dong

Liu

et al. 2022

Cells

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The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic effectiveness for chemoresistance of the DNA alkylating agent temozolomide (TMZ) in glioblastoma (GB). However, the underlying mechanisms of PTEN’s interconnected role in the cytoplasm and nucleus in TMZ resistance are still unclear. In this study, we report that TMZ−induced PTEN nuclear import depends on PTEN ubiquitylation modification by Smurf1. The Smurf1 suppression decreases the TMZ−induced PTEN nuclear translocation and enhances the DNA damage. In addition, Smurf1 degrades cytoplasmic PTEN K289E (the nuclear−import−deficient PTEN mutant) to activate the PI3K/Akt pathway under TMZ treatment. Altogether, Smurf1 interconnectedly promotes PTEN nuclear function (DNA repair) and cytoplasmic function (activation of PI3K/Akt pathway) to resist TMZ. These results provide a proof−of−concept demonstration for a potential strategy to overcome the TMZ resistance in PTEN wild−type GB patients by targeting Smurf1.

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“…The medium was supplemented with penicillin (100 U/ml) and streptomycin (100 mg/ml). All cells were cultured at 37°C in 5% CO 2 ( 31 ).…”

Section: Methodsmentioning

confidence: 99%

ADAMDEC1 accelerates GBM progression via activation of the MMP2-related pathway

Wang

Sun

et al. 2022

Front. Oncol.

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The ADAM (a disintegrin and metalloprotease) gene-related family including ADAM, ADAMTS, and ADAM-like decysin-1 has been reported to play an important role in the pathogenesis of multiple diseases, including cancers (lung cancer, gliomas, colorectal cancer, and gastrointestinal cancer). However, its biological role in gliomas remains largely unknown. Here, we aimed to investigate the biological functions and potential mechanism of ADAMDEC1 in gliomas. The mRNA and protein expression levels of ADAMDEC1 were upregulated in glioma tissues and cell lines. ADAMDEC1 showed a phenomenon of “abundance and disappear” expression in gliomas and normal tissues in that the higher the expression of ADAMDEC1 presented, the higher the malignancy of gliomas and the worse the prognosis. High expression of ADAMDEC1 was associated with immune response. Knockdown of ADAMDEC1 could decrease the proliferation and colony-forming ability of LN229 cells, whereas ADAMDEC1 overexpression has opposite effects in LN229 cells in vitro. Furthermore, we identified that ADAMDEC1 accelerates GBM progression via the activation of the MMP2 pathway. In the present study, we found that the expression levels of ADAMDEC1 were significantly elevated compared with other ADAMs by analyzing the expression levels of ADAM family proteins in gliomas. This suggests that ADAMDEC1 has potential as a glioma clinical marker and immunotherapy target.

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Acquired temozolomide resistance in MGMTlow gliomas is associated with regulation of homologous recombination repair by ROCK2

Cited by 13 publications

References 47 publications

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

ADAMDEC1 accelerates GBM progression via activation of the MMP2-related pathway

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