Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors

Jackson, Christopher B.; Noorbakhsh, Seth; Sundaram, Ranjini K.; Kalathil, Aravind N.; Ganesa, Sachita; Jia, Lanqi; Breslin, Hank; Burgenske, Danielle M.; Gilad, Oren; Sarkaria, Jann N.; Bindra, Ranjit S.

doi:10.1158/0008-5472.can-18-3394

Cited by 51 publications

(54 citation statements)

References 17 publications

(24 reference statements)

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“…Historically, these tumors have been treated with maximal surgical resection, followed by external beam radiation therapy. Survival was extended by adding the alkylator temozolomide (TMZ) ( Arora and Somasundaram, 2019 ; Jackson et al., 2019 ; Nam and de Groot, 2017 ; Thomas et al., 2017 ; Zhang et al., 2012b ). Surgery followed by concurrent chemo-radiation remain the standard of care for patients with GBM.…”

Section: Introductionmentioning

confidence: 99%

Tunneling Nanotubes Mediate Adaptation of Glioblastoma Cells to Temozolomide and Ionizing Radiation Treatment

Valdebenito

Audia²,

Bhat³

et al. 2020

iScience

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Summary Glioblastoma (GBM) is the most prevalent and aggressive tumor in the central nervous system. Surgical resection followed by concurrent radiotherapy (ionizing radiation [IR]) and temozolomide (TMZ) is the standard of care for GBM. However, a large subset of patients offer resistance or become adapted to TMZ due mainly to the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). Thus, alternative mechanisms of MGMT deregulation have been proposed but are heretofore unproven. We show that heterogeneous GBM cells express tunneling nanotubes (TNTs) upon oxidative stress and TMZ/IR treatment. We identified that MGMT protein diffused from resistant to sensitive cells upon exposure to TMZ/IR, resulting in protection against cytotoxic therapy in a TNT-dependent manner. In vivo analysis of resected GBM tumors support our hypothesis that the MGMT protein, but not its mRNA, was associated with TNT biomarkers. We propose that targeting TNT formation could be an innovative strategy to overcome treatment resistance in GBM.

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Section: Introductionmentioning

confidence: 99%

Tunneling Nanotubes Mediate Adaptation of Glioblastoma Cells to Temozolomide and Ionizing Radiation Treatment

Valdebenito

Audia²,

Bhat³

et al. 2020

iScience

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“…While the clinical significance of STAG2 deficiency in human cancers remains under investigation, preclinical data have shown a synthetic lethality conferred by STAG2 mutations with DNA DSB repair genes, including increased sensitivity to PARP and ATR inhibitors 6,27 . This has been previously studied in other biomarkers of defective DNA damage repair, including IDH1/2 mutational status and MGMT promoter methylation [28][29][30] . On the other hand, STAG2 deficient cancer cells have also been shown to exhibit increased sensitivity in vitro to ionizing radiation and traditional chemotherapeutic agents, including temozolomide 6 , which contrasts with the aggressive clinical course of our patient.…”

Section: Discussionmentioning

confidence: 99%

Persistent STAG2 mutation despite multimodal therapy in recurrent pediatric glioblastoma

et al. 2020

Self Cite

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Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from wholeexome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious STAG2 mutation, whose deficiency in preclinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an EGFR mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently STAG2 mutated clone, with rare mutations in PTPN11 and BRAF, the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying STAG2 deficiency. As such, this case represents a novel report following the clinical and genetic progression of a STAG2 mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although STAG2 deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing preclinical data supporting a role for STAG2 mutations in gliomagenesis and resistance to standard therapies.

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“…It is also important to determine the role of methylation status of MGMT and DDR genes in DDR inhibitor clinical trials. For example, TMZ preferentially sensitizes MGMT-deficient tumor cells to ATR inhibition in preclinical models, 46 but similar observations have not been described with DNA-PK or ATM inhibition. We recommend inclusion of both MGMT promoter methylated and unmethylated GBM tumors in early phase clinical trials and to stratify based on MGMT status in order to detect early signals regarding the role of MGMT status in determining response to DDR inhibitors.…”

Section: Strategies For Successful Clinical Development Of Ddr Inhibimentioning

confidence: 93%

“… 45 Jackson et al demonstrated that TMZ activated ATR in an MGMT-dependent manner and that treatment of MGMT-deficient cells with TMZ increased sensitivity to ATR inhibitors in in vitro and in vivo models of GBM cell lines. 46 The role of MGMT promoter methylation status in determining response to DDR inhibitors needs to be investigated further in clinical trials.…”

Section: Atr Inhibitorsmentioning

confidence: 99%

The promise of DNA damage response inhibitors for the treatment of glioblastoma

Majd

Yap

Koul

et al. 2021

Neuro-Oncology Advances

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Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM. The inter- and intra-tumoral heterogeneity of GBM, inadequate drug concentrations in the tumor owing to the blood-brain barrier, redundant signaling pathways contributing to resistance to conventional therapies, and an immunosuppressive tumor microenvironment, have all hindered the development of novel therapies for GBM. Given the high frequency of DNA damage pathway alterations in GBM, researchers have focused their efforts on pharmacologically targeting key enzymes, including poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase, ataxia telangiectasia-mutated, and ataxia telangiectasia and Rad3-related. The mainstays of GBM treatment, ionizing radiation and alkylating chemotherapy, generate DNA damage that is repaired through the upregulation and activation of DNA damage response (DDR) enzymes. Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.

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Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors

Cited by 51 publications

References 17 publications

Tunneling Nanotubes Mediate Adaptation of Glioblastoma Cells to Temozolomide and Ionizing Radiation Treatment

Tunneling Nanotubes Mediate Adaptation of Glioblastoma Cells to Temozolomide and Ionizing Radiation Treatment

Persistent STAG2 mutation despite multimodal therapy in recurrent pediatric glioblastoma

The promise of DNA damage response inhibitors for the treatment of glioblastoma

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