MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Erice, Oihane; Smith, Michael P.; White, Robert L.; Goicoechea, Ibai; Barriuso, Jorge; Jones, Chris; Margison, Geoffrey P.; Acosta, Juan Carlos; Wellbrock, Claudia; Arozarena, Imanol

doi:10.1158/1535-7163.mct-14-0810

Cited by 36 publications

(30 citation statements)

References 49 publications

(67 reference statements)

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“…A preceding paper showed that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not because MGMT-negative cells are primarily killed by unrepaired O6-methyl-guanine generated by low dose of temozolomide [42]. …”

Section: Resultsmentioning

confidence: 99%

Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition

et al. 2016

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Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs.

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Section: Resultsmentioning

confidence: 99%

Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition

et al. 2016

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“…TMZ resistance has been linked to increased expression of O6-methylguanine DNA methyltransferase (MGMT) [27,28,29]. To investigate whether BIS-mediated HSF1 downregulation had an effect on MGMT, we analyzed MGMT expression using qRT-PCR in A172 and U87 cells.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

Yun

Lee

2017

IJMS

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Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS, although it is still unclear whether this interaction is critical in the regulation of glioblastoma stem cells (GSCs). In this study, we examined whether small interfering RNA-mediated BIS knockdown decreased protein levels of HSF1 and subsequent nuclear localization under GSC-like sphere (SP)-forming conditions. Consistent with BIS depletion, HSF1 knockdown also reduced sex determining region Y (SRY)-box 2 (SOX2) expression, a marker of stemness, accompanying the decrease in SP-forming ability and matrix metalloprotease 2 (MMP2) activity. When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased. Taken together, our findings suggest that targeting BIS or HSF1 could be a viable therapeutic strategy for GSCs resistant to conventional TMZ treatment.

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“…Attempts to overcome resistance to TMZ led to several approaches including direct inhibition of MGMT, blockade of abasic sites, PARP inhibition etc. [ 23 , 32 – 38 ]. Alternative targets to sensitize cells to TMZ such as the epidermal growth factor receptor (EGFR) have been investigated by our laboratory [ 11 , 39 – 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…N7-methylguanine and N3-methyladenine) are processed by the base excision repair machinery, in which PARP plays a central role. It has already been shown that in MGMT-proficient cells, PARP inhibition sensitized cells to TMZ [ 21 – 23 ] and this was believed to be due to the cytotoxic effects of unrepaired alkylated bases other than O6-methylguanine. Accordingly, given that the mechanism of cell-killing by the designed combi-molecule in BRCA1/2 depends on PARP inhibition, we also sought to determine whether the MGMT status of the cells would influence the potency of these dual PARP-DNA targeting combi-molecules.…”

Section: Introductionmentioning

confidence: 99%

A type I combi-targeting approach for the design of molecules with enhanced potency against BRCA1/2 mutant- and O6-methylguanine-DNA methyltransferase (mgmt)- expressing tumour cells

2017

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BackgroundMutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leads to cell death due to the absence of compensatory DNA repair mechanism. The potency of PARP inhibitors has now been clinically proven. However, disappointingly, acquired resistance mediated by the reactivation of wild type BRCA1/2 has been reported. In order to improve their efficacy, trials are ongoing to explore their combinations with temozolomide (TMZ). Here, in order to enhance potency in BRCA1/2-mutant cells, we report on the design of single molecules termed “combi-molecules” capable of not only inhibiting PARP but also damaging DNA like TMZ, which is known to induce a large number of DNA adducts. The majority of these lesions are processed through PARP-dependent base-excision repair machinery. Paradoxically, the least abundant lesion, the O6-methylguanine adduct is the most cytotoxic. Its repair by the O6-methylguanine DNA methyl transferase (MGMT) confers robust resistance to TMZ. Thus, we surmise that a combi-molecule designed to generate the same DNA adducts as TMZ, with an additional ability to block PARP, could induce BRCA1/2 mutant selective potency and a growth inhibitory profile independent of MGMT status.MethodsThe hydrolysis of EG22 and its stabilized form ZSM02 was analyzed by HPLC and fluorescence spectroscopy. Growth inhibitory potency was determined by SRB assay. PARP inhibition was determined by an enzyme assay and DNA damage by the comet assay. Subcellular distribution was visualized by confocal microscopy.ResultsStudies on EG22 showed that: (a) it inflicted anomalously higher levels of DNA damage than TMZ (b) it induced PARP inhibitory potency in the same range as ANI, a known PARP inhibitor (IC50 = 0.10 μM) (c) it showed strong potency in both BRCA1/2 wild type and mutated cells with 6-fold selectivity for the mutants and it was 65–303-fold more potent than TMZ and 4–63-fold than ANI alone and 3–47-fold than their corresponding equimolar combinations and (d) its potency was independent of MGMT expression.ConclusionThe results in toto suggest that a combi-molecular approach directed at blocking PARP and damaging DNA can lead to single molecules with selective and enhanced potency against BRCA1/2 mutant and with activity independent of MGMT, the major predictive biomarker for resistance to TMZ.

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MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Cited by 36 publications

References 49 publications

Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition

Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition

Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

A type I combi-targeting approach for the design of molecules with enhanced potency against BRCA1/2 mutant- and O6-methylguanine-DNA methyltransferase (mgmt)- expressing tumour cells

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