DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies

Rominiyi, Ola; Collis, Spencer J.

doi:10.1002/1878-0261.13020

Cited by 21 publications

(19 citation statements)

References 257 publications

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“…However, studies have recently shown that MGMT overexpression is not the only determinant contributing to GBM resistance to TMZ [5]. Other factors, such as the advent of GSCs, overactivation of DNA repair pathways, favorable autophagy, decreased drug influx and increased drug efflux, facilitate drug resistance in TMZ in addition to MGMT overexpression [46][47][48][49][50][51]. GSCs exhibit the capacity for self-renewal, immortal propagation and multilineage differentiation [52].…”

Section: Discussionmentioning

confidence: 99%

PDIA3P1 promotes Temozolomide resistance in glioblastoma by inhibiting C/EBPβ degradation to facilitate proneural-to-mesenchymal transition

Gao

Fan

et al. 2022

J Exp Clin Cancer Res

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Background Resistance to temozolomide (TMZ) is a major obstacle to preventing glioblastoma (GBM) recurrence after surgery. Although long noncoding RNAs (lncRNAs) play a variety of roles in GBM, the lncRNAs that regulate TMZ resistance have not yet been clearly elucidated. This study aims to identify lncRNAs that may affect TMZ treatment sensitivity and to explore novel therapeutic strategies to overcome TMZ resistance in GBM. Methods LncRNAs associated with TMZ resistance were identified using the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Quantitative real-time PCR (qRT–PCR) was used to determine the expression of PDIA3P1 in TMZ-resistant and TMZ-sensitive GBM cell lines. Both gain-of-function and loss-of-function studies were used to assess the effects of PDIA3P1 on TMZ resistance using in vitro and in vivo assays. Glioma stem cells (GSCs) were used to determine the effect of PDIA3P1 on the GBM subtype. The hypothesis that PDIA3P1 promotes proneural-to-mesenchymal transition (PMT) was established using bioinformatics analysis and functional experiments. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between PDIA3P1 and C/EBPβ. The posttranslational modification mechanism of C/EBPβ was verified using ubiquitination and coimmunoprecipitation (co-IP) experiments. CompuSyn was leveraged to calculate the combination index (CI), and the antitumor effect of TMZ combined with nefllamapimod (NEF) was validated both in vitro and in vivo. Results We identified a lncRNA, PDIA3P1, which was upregulated in TMZ-resistant GBM cell lines. Overexpression of PDIA3P1 promoted the acquisition of TMZ resistance, whereas knockdown of PDIA3P1 restored TMZ sensitivity. PDIA3P1 was upregulated in MES-GBM, promoted PMT progression in GSCs, and caused GBMs to be more resistant to TMZ treatment. Mechanistically, PDIA3P1 disrupted the C/EBPβ-MDM2 complex and stabilized the C/EBPβ protein by preventing MDM2-mediated ubiquitination. Expression of PDIA3P1 was upregulated in a time- and concentration-dependent manner in response to TMZ treatment, and TMZ-induced upregulation of PDIA3P1 was mediated by the p38α-MAPK signaling pathway. NEF is a small molecule drug that specifically targets p38α with excellent blood–brain barrier (BBB) permeability. NEF blocked TMZ-responsive PDIA3P1 upregulation and produced synergistic effects when combined with TMZ at specific concentrations. The combination of TMZ and NEF exhibited excellent synergistic antitumor effects both in vitro and in vivo. Conclusion PDIA3P1 promotes PMT by stabilizing C/EBPβ, reducing the sensitivity of GBM cells to TMZ treatment. NEF inhibits TMZ-responsive PDIA3P1 upregulation, and NEF combined with TMZ provides better antitumor effects.

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Section: Discussionmentioning

confidence: 99%

PDIA3P1 promotes Temozolomide resistance in glioblastoma by inhibiting C/EBPβ degradation to facilitate proneural-to-mesenchymal transition

Gao

Fan

et al. 2022

J Exp Clin Cancer Res

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“…In the SSB, PARP1 plays a central role in the detection and repair of the pathway (Ref. 9). SSB and base modification form multiple DNA lesions, favouring a change in base-pairing properties and causing spontaneous mutations (Ref.…”

Section: Dna Damage Response Induced By Temozolomide and Radiotherapymentioning

confidence: 99%

“…DSBs are repaired through two mechanisms, the NHEJ and HR DNA repair pathways (Ref. 9). The HR mechanisms takes place in late G1 and G2 phases and is using the sister chromatid as a DNA replication template to correct the damage (Refs 9, 68).…”

Section: Dna Damage Response Induced By Temozolomide and Radiotherapymentioning

confidence: 99%

“…This allowed the identification of specific genetic anomalies, present in both the coding and non-coding regions of the genome. Therefore, the repository of therapeutic targets expended, supporting the development of new targeted therapies against GBM that are looking at specific genetic event inhibition or are targeting complex molecular pathways such as DDR (Refs 7–9).…”

Section: Introductionmentioning

confidence: 99%

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New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs

Pirlog,

Ilut,

Pirlog

et al. 2023

Expert Rev. Mol. Med.

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Background. Glioblastoma (GBM) is the most frequent type of primary brain cancer, having a median survival of only 15 months. The current standard of care includes a combination of surgery, radiotherapy (RT) and chemotherapy with temozolomide, but with limited results. Moreover, multiple studies have shown that tumour relapse and resistance to classic therapeutic approaches are common events that occur in the majority of patients, and eventually leading to death. New approaches to better understand the intricated tumour biology involved in GBM are needed in order to develop personalised treatment approaches. Advances in cancer biology have widen our understanding over the GBM genome and allowing a better classification of these tumours based on their molecular profile. Methods. A new targeted therapeutic approach that is currently investigated in multiple clinical trials in GBM is represented by molecules that target various defects in the DNA damage repair (DDR) pathway, a mechanism activated by endogenous and exogenous factors that induce alteration of DNA, and is involved for the development of chemotherapy and RT resistance. This intricate pathway is regulated by p53, two important kinases ATR and ATM and non-coding RNAs including microRNAs, long-non-coding RNAs and circular RNAs that regulate the expression of all the proteins involved in the pathway. Results. Currently, the most studied DDR inhibitors are represented by PARP inhibitors (PARPi) with important results in ovarian and breast cancer. PARPi are a class of tumour agnostic drugs that showed their efficacy also in other localisations such as colon and prostate tumours that have a molecular signature associated with genomic instability. These inhibitors induce the accumulation of intracellular DNA damage, cell cycle arrest, mitotic catastrophe and apoptosis. Conclusions. This study aims to provide an integrated image of the DDR pathway in glioblastoma under physiological and treatment pressure with a focus of the regulatory roles of ncRNAs. The DDR inhibitors are emerging as an important new therapeutic approach for tumours with genomic instability and alterations in DDR pathways. The first clinical trials with PARPi in GBM are currently ongoing and will be presented in the article. Moreover, we consider that by incorporating the regulatory network in the DDR pathway in GBM we can fill the missing gaps that limited previous attempts to effectively target it in brain tumours. An overview of the importance of ncRNAs in GBM and DDR physiology and how they are interconnected is presented.

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“… 4 In 2016, there were 330 000 CNS cancer cases, particularly brain tumors. 5 Since currently brain tumors lead to 190 000 deaths per year, 6 there is huge demand to find therapies that allow a better understanding of tumour cell behavior and, subsequently, implementation of targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

Methylcellulose/agarose hydrogel loaded with short electrospun PLLA/laminin fibers as an injectable scaffold for tissue engineering/3D cell culture model for tumour therapies

et al. 2023

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DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies

Cited by 21 publications

References 257 publications

PDIA3P1 promotes Temozolomide resistance in glioblastoma by inhibiting C/EBPβ degradation to facilitate proneural-to-mesenchymal transition

PDIA3P1 promotes Temozolomide resistance in glioblastoma by inhibiting C/EBPβ degradation to facilitate proneural-to-mesenchymal transition

New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs

Methylcellulose/agarose hydrogel loaded with short electrospun PLLA/laminin fibers as an injectable scaffold for tissue engineering/3D cell culture model for tumour therapies

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