DNA repair pathways as targets for cancer therapy

Helleday, Thomas; Petermann, Eva; Lundin, Cecilia; Hodgson, Ben; Sharma, Ricky A.

doi:10.1038/nrc2342

Cited by 1,463 publications

(1,368 citation statements)

References 127 publications

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“…53,54 Interfering with DNA repair as a means of tumor cell chemosensitization has long been proposed as a promising anticancer strategy. 55,56 However, the development of specific inhibitors of DNA repair factors is far from being trivial. Moreover, targeted inhibitors always bear the risk of resistance development, either by compensatory mutations within the target itself, or by activation of alternative repair pathways.…”

Section: Ganetespib Carboplatin Combinationmentioning

confidence: 99%

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation. Live-cell microscopy revealed chromosome fragmentation occurring to a dramatic degree when cells condensed their chromatin in preparation for mitosis, followed by cell death in mitosis or upon aberrant exit from mitosis. HSP90 inhibition caused the rapid decay of key components of the Fanconi anemia pathway required for repair of carboplatin-induced interstrand crosslinks (ICLs), as well as of cell cycle checkpoint mediators. Overexpressing FancA rescued the DNA damage induced by the drug combination, indicating that FancA is indeed a key client of Hsp90 that enables cancer cell survival in the presence of ICLs. Conversely, depletion of nuclease DNA2 prevented chromosomal fragmentation, pointing to an imbalance of defective repair in the face of uncontrolled nuclease activity as mechanistic basis for the observed premitotic DNA fragmentation. Importantly, the drug combination induced robust antitumor activity in xenograft models, again accompanied with depletion of FancA. In sum, our findings indicate that ganetespib strongly potentiates the antitumor efficacy of carboplatin by causing combined inhibition of DNA repair and cell cycle control mechanisms, thus triggering global chromosome disruption, aberrant mitosis and cell death. 6 This provides a strong rationale for HSP90 inhibitors in cancer therapy 7 and raises the possibility that HSP90 inhibitors can be used in combination with DNAdamaging chemotherapeutics. 8 Ovarian cancer is among the most common gynecological tumor types and carries the worst prognosis. HSP90 is highly expressed in advanced ovarian carcinoma 9 and thus constitutes a potential therapeutic drug target. 10 In support, HSP90 inhibitors were found effective against ovarian cancer in preclinical models, 11-14 alone or in combination with conventional chemotherapy. 15,16 Carboplatin is the key component of all current first-line therapies for ovarian carcinoma. However, while initially often responding with regression, most tumors relapse and develop resistance within less than a year. 17,18 Like other platinum compounds, carboplatin acts by forming crosslinks within DNA. 17 Platinum compounds form intrastrand DNA lesions but also interstrand crosslinks (ICLs) by covalently linking opposite DNA strands. Such ICLs represent major obstacles to the DNA replication fork 19 and are therefore considered the principal toxic lesion of carboplatin's mode of action. The ICLs can only be removed by a sophisticated DNA repair systemthe Fanconi ...

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Section: Ganetespib Carboplatin Combinationmentioning

confidence: 99%

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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“…5,6 Occurrence of resistance to DNA alkylating agents in cancer cells may be due to decreased uptake of the agent into cells, increased drug extrusion, drug inactivation in the cells due to chemical instability, or quick repair of DNA lesions. 7,8 Additionally, methylated adducts formed by drug treatment can be removed and repaired by O 6 -methylguanine-DNA methyltransferase (MGMT), which is responsible for drug resistance to temozolamide and BCNU. 7,9 Although toxicity and resistance are the major problems associated with alkylating agent chemotherapy, numerous alkylating agents remain the first line drugs to treat a variety of cancers.…”

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confidence: 99%

“…7,8 Additionally, methylated adducts formed by drug treatment can be removed and repaired by O 6 -methylguanine-DNA methyltransferase (MGMT), which is responsible for drug resistance to temozolamide and BCNU. 7,9 Although toxicity and resistance are the major problems associated with alkylating agent chemotherapy, numerous alkylating agents remain the first line drugs to treat a variety of cancers. 6,10 Newly designed alkylating agents with increased efficacy and decreased adverse side effects are needed to improve the treatment of cancer.…”

mentioning

confidence: 99%

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Sanjiv

Suman

et al. 2011

Intl Journal of Cancer

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Oral cancer is the fourth-most common cause of death in males and overall the sixth-most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5-fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer. Here, we demonstrated that derivatives of 3a-aza-cyclopenta[a]indene, a class of newly synthesized alkylating agents, may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on in vivo xenografts. Among them, BO-1090, bis(hydroxymethyl)-3a-aza-cyclopenta[a]indene derivative, targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine-based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single-stranded breaks (Comet assay) and double-stranded breaks (c-H2AX focus formation). Following DNA damage, BO-1090 induced G1/S-phase arrest and apoptosis in oral cancer cell lines. The therapeutic potential of BO-1090 was tested in mice that received a xenograft of oral cavity cancer cell lines (SAS or Cal 27 cells). Intravenous injection of BO-1090 significantly suppressed tumor growth in comparison to control mice. BO-1090 also significantly reduced the tumor burden in orthotopic mouse models using SAS cells. There was no significant adverse effect of BO-1090 treatment with this dosage based on whole blood count, biochemical enzyme profiles in plasma and histopathology of various organs in mouse. Taken together, our current results demonstrate that B0-1090 may have potential as a treatment for oral cavity cancer.Oral cavity cancer involving the lesions occurred in the tongue, oropharynx and floor of the mouth is a prevalent type of cancer in developing countries such as India, Pakistan, Bangladesh and Taiwan. 1 In south-central Asia, it is the third-most common cancer, with an average incidence rate of 1 to 10 per 100,000 people. The incidence of oral cancer is also increasing in developed countries. 2 The treatments of oral cancer include surgery, radiation or chemotherapy, depending on the stage and nature of the tumor. 3,4 Unfortunately, only marginal improvement is seen in many patients, and a complete cure is often not achieved. Half of the patients diagnosed with oral cancer succumb to death within 5 years, and for those who survive, the quality of life remains poor. 1 Thus, development of a drug specific for oral cavity cancer is needed so that substantial improvement in treatment can be achieved.The cytotoxic and antitumor properties of alkylating agents are due to their ability to covalently bind to DNA. There are two types of DNA alkylating agents, monofunctional and bifunctional agents. Monofunctional alkylating agents mainly damage DNA by forming methylated adducts, whereas the damage induced by bifunctional alkylating agents includes monoadducts, intrastrand crosslinks and interstrand crossli...

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“…The exponentially fast increase of small mutational loads indicates that reducing instability levels in hope for progression delay might result in rapid re‐exploration of the mutator phenotype. On the other hand, pushing instability beyond optimal levels, even if a critical point is not trespassed (Solé & Deisboeck, 2004), might render tumour cells too unstable, and there exist relevant efforts towards using DNA repair inhibitors to produce critical instability levels (Helleday et al., 2008). …”

Section: Discussionmentioning

confidence: 99%

Adaptive dynamics of unstable cancer populations: The canonical equation

Aguadé-Gorgorió

Solé

2018

Evolutionary Applications

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In most instances of tumour development, genetic instability plays a role in allowing cancer cell populations to respond to selection barriers, such as physical constraints or immune responses, and rapidly adapt to an always changing environment. Modelling instability is a nontrivial task, since by definition evolving instability leads to changes in the underlying landscape. In this article, we explore mathematically a simple version of unstable tumour progression using the formalism of adaptive dynamics (AD) where selection and mutation are explicitly coupled. Using a set of basic fitness landscapes, the so‐called canonical equation for the evolution of genetic instability on a minimal scenario associated with a population of unstable cells is derived. We obtain explicit expressions for the evolution of mutation probabilities, and the implications of the model on further experimental studies and potential mutagenic therapies are discussed.

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DNA repair pathways as targets for cancer therapy

Cited by 1,463 publications

References 127 publications

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Adaptive dynamics of unstable cancer populations: The canonical equation

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