Tumor <i>O</i>6-methylguanine-DNA Methyltransferase Inactivation by Oral Lomeguatrib

Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide. As a consequence, clinical responses are generally poor. Such resistance is partly due to the ability of cancer cells to use a variety of DNA repair enzymes to maintain cell viability. Particularly, the expression of MGMT has been linked to temozolomide resistance, but cotargeting MGMT has proven difficult due to dose-limiting toxicities. Here, we show that the MGMT-mediated resistance of cancer cells is profoundly dependent on the DNA repair enzyme PARP. Both in vitro and in vivo, we observe that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not. In melanoma cells, temozolomide induced an antiproliferative senescent response, which was greatly enhanced by PARPi in MGMTpositive cells. In summary, we provide compelling evidence to suggest that the stratification of patients with cancer upon the MGMT status would enhance the success of combination treatments using temozolomide and PARPi.

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“…After incubation, assay samples were processed as described previously in (ref. 28) and radioactivity quantified by scintillation counting.…”

Section: Mgmt Activity Assaysmentioning

confidence: 99%

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Erice

Smith

White

et al. 2015

Molecular Cancer Therapeutics

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“…In order to establish if different doses of O 6 -BTG would be needed to deplete MGMT activity in prostate, colorectal or brain tumours [109], a total of 32 patients were given a single dose of O 6 -BTG orally approximately 12 h before resection of their primary tumour. Complete inactivation of MGMT in prostate and colorectal cancers required a dose of 120 mg, and in CNS tumours, a dose of 160 mg O 6 -BTG [109].…”

Section: Phase I and Ii Trialsmentioning

confidence: 99%

“…Complete inactivation of MGMT in prostate and colorectal cancers required a dose of 120 mg, and in CNS tumours, a dose of 160 mg O 6 -BTG [109]. This indicates that the doses used in the phase II studies (40-80 mg) may have been lower than optimal.…”

Section: Phase I and Ii Trialsmentioning

confidence: 99%

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Kaina

Margison

Christmann

2010

Cell. Mol. Life Sci.

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124

116

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O (6)-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O (6)-methylguanine and O (6)-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O (6)-benzylguanine and O (6)-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.

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“…Since one molecule of MGMT removes only one alkyl molecule, an excess of DNA adducts at the O 6 -position could completely deplete MGMT [29,30]. The stoichiometric and irreversible transfer of adducts to internal cysteine residues at position 145 prevents GC AT transitions or [41,43,44] Melanoma in vivo [38,39] Pediatric/solid tumors Phase I [45] Glioblastoma A clinical trial [40] Lomeguatrib TMZ Melanoma A clinical trial [52] Prostate, CNS, colorectal cancer A clinical trial [53] Acute leukemia in vitro [49] Pancreatic Phase I [50] Breast cancer in vitro/in vivo [48] Ovarian cancer in vitro [47] Antiepileptic drugs…”

Section: Mgmt Activity Determines Tmz Resistancementioning

confidence: 99%

Strategies to Improve the Killing of Tumors Using Temozolomide: Targeting the DNA Repair Protein MGMT

Jiang

Li²,

Xin³

et al. 2012

CMC

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Alkylating agents such as temozolomide (TMZ) are effective anticancer drugs for treating a variety of solid tumors including melanoma, glioma, and astrocytoma. TMZ exerts its effects mainly via the mutagenic product O(6)-methylguanine, a cytotoxic DNA lesion. This damage may be repaired by the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT), a key player in the resistance of cancers to TMZ. Several strategies are presently being pursued to improve the killing of tumor cells by TMZ, with inhibition of MGMT being the most promising. In this review, we provide an overview of recent advances in this field.

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Tumor O6-methylguanine-DNA Methyltransferase Inactivation by Oral Lomeguatrib

Cited by 33 publications

References 15 publications

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Strategies to Improve the Killing of Tumors Using Temozolomide: Targeting the DNA Repair Protein MGMT

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