Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer

Mishra, Akaash K.; Dormi, Silvana S.; Turchi, Alaina M.; Woods, Derek S.; Turchi, John J.

doi:10.1016/j.bcp.2014.10.013

Cited by 44 publications

(72 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7). Further synthetic structural modification of TDRL-505 generated several analogs and TDRL-551 was identified as the most potent compound of the series (Mishra, Dormi, Turchi, Woods, & Turchi, 2014). TDRL-551 blocks the RPA-DNA interaction, displays modest single agent activity in lung and ovarian cancer cell lines and also synergizes with cisplatin and etoposide.…”

Section: Ner Inhibitors and Combination Pt-therapymentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

Self Cite

325

282

View full text Add to dashboard Cite

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.

show abstract

Section: Ner Inhibitors and Combination Pt-therapymentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

Self Cite

325

282

View full text Add to dashboard Cite

show abstract

“…Ovarian cancer overall comprises a variety of tumour types with different histopathological features and biological behaviors . Although most ovarian cancer patients present with advanced‐stage disease, response to front‐line Pt‐based chemotherapy is high, of the order of 75% . Cisplatin is a DNA‐damage drug and acts against cancer by stimulating reactions in cytoplasm and the nucleus responsible for injury repair, cell cycles, and apoptosis .…”

Section: Introductionmentioning

confidence: 99%

“…1,7 Although most ovarian cancer patients present with advanced-stage disease, response to front-line Pt-based chemotherapy is high, of the order of 75%. 8 Cisplatin is a DNA-damage drug and acts against cancer by stimulating reactions in cytoplasm and the nucleus responsible for injury repair, cell cycles, and apoptosis. 9,10 Cisplatin is frequently used in ovarian cancer treatment, and resistance is easily seen in patients during treatment.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the CSF‐1 receptor sensitizes ovarian cancer cells to cisplatin

Jin

et al. 2018

Cell Biochemistry & Function

View full text Add to dashboard Cite

Ovarian cancer is one of the most common female malignancies, and cisplatin-based chemotherapy is routinely used in locally advanced ovarian cancer patients. Acquired or de novo cisplatin resistance remains the barrier to patient survival, and the mechanisms of cisplatin resistance are still not well understood. In the current study, we found that colony-stimulating-factor-1 receptor (CSF-1R) was upregulated in cisplatin-resistant SK-OV-3 and CaoV-3 cells. Colony-stimulating-factor-1 receptor knockdown suppressed proliferation and enhanced apoptosis in cisplatin-resistant SK-OV-3 and CaoV-3 cells. However, CSF-1R overexpression had inverse effects. While parental SK-OV-3 and CaoV-3 cells were more resistant to cisplatin after CSF-1R overexpression, CSF-1R knockdown in SK-OV-3 and CaoV-3 cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that CSF-1R significantly promoted active AKT and ERK1/2 signalling pathways in cisplatin-resistant cells. Furthermore, a combination of cisplatin and CSF-1R inhibitor effectively inhibited tumour growth in xenografts. Taken together, our results provide the first evidence that CSF-1R inhibition can sensitize cisplatin-refractory ovarian cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumours.

show abstract

“…RPA is important for both NER and HR, and RPA inhibition causes cell cycle arrest, cell death, and enhances sensitivity to cisplatin and etoposide (106,108). This suggests that RPA inhibitors could be combined with PARP1 inhibitors to mediate synthetic lethality in cancers with nonmutated BRCA1/2.…”

Section: Drugging Nucleotide Excision Repairmentioning

confidence: 99%

Drugging the Cancers Addicted to DNA Repair

Nickoloff

Jones

Lee

et al. 2017

JNCI: Journal of the National Cancer Institute

137

114

View full text Add to dashboard Cite

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.

show abstract

Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer

Cited by 44 publications

References 34 publications

DNA repair targeted therapy: The past or future of cancer treatment?

DNA repair targeted therapy: The past or future of cancer treatment?

Inhibition of the CSF‐1 receptor sensitizes ovarian cancer cells to cisplatin

Drugging the Cancers Addicted to DNA Repair

Contact Info

Product

Resources

About