FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Mesquita, Katia A.; Ali, Reem; Doherty, Rachel; Toss, Michael S.; Miligy, Islam M.; Alblihy, Adel; Dorjsuren, Dorjbal; Simeonov, Anton; Jadhav, Ajit; Wilson, David M.; Hickson, Ian; Tatum, Natalie J.; Rakha, Emad A.

doi:10.3390/cancers13081866

Cited by 14 publications

(23 citation statements)

References 47 publications

(43 reference statements)

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“…Flap endonuclease 1 (FEN1), a member of the XPG/RAD2 endonuclease family, is another protein involved in BER whose overexpression in cancer is associated with an aggressive phenotype and platinum-agent resistance. A pre-clinical study showed that the depletion of FEN1 sensitizes previously resistant epithelial ovarian cancer cells and identified several small molecules that could be developed as FEN1 inhibitors [ 134 ].…”

Section: Current Treatment Strategies and Future Perspectivesmentioning

confidence: 99%

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

Kiss

Xia

Acklin

2021

IJMS

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Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.

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Section: Current Treatment Strategies and Future Perspectivesmentioning

confidence: 99%

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

Kiss

Xia

Acklin

2021

IJMS

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“…[ 41 ]. Figure 3 shows the interaction between FEN1 and different proteins [ 10 , 16 ]. When interacting with PCNA, FEN1 will be recruited to the replication defect region to excise the RNA primers and repair the DNA BER sites.…”

Section: Overview Of Fen1mentioning

confidence: 99%

“…FEN1 overexpression is associated with an increased aggressive phenotype and poor prognosis of cancer after cisplatin chemotherapy, while inhibition of Pol β or XRCC1 can enhance the sensitivity of ovarian cancer to cisplatin treatment [ 16 ]. The abovementioned study found that FEN1 was synthetically lethal in Pol β deficiency but not synthetically lethal in XRCC1, ATM or MRE11 deficiencies.…”

Section: Development Of Fen1 Inhibitorsmentioning

confidence: 99%

“…When cisplatin was used to treat ovarian cancer, it was found that FEN1 expression was strongly induced and that the nuclear translocation of FEN1 depended on the physical interaction with Importin β. Loss; gene inactivation or inhibition of FEN1 could re-sensitize platinum-resistant ovarian cancer cells to cisplatin [ 16 ]. Ectopic expression of FEN1 in breast cancer enhances adriamycin resistance.…”

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

Yang

Guo

2022

Biomolecules

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DNA damage repair plays a key role in maintaining genomic stability and integrity. Flap endonuclease 1 (FEN1) is a core protein in the base excision repair (BER) pathway and participates in Okazaki fragment maturation during DNA replication. Several studies have implicated FEN1 in the regulation of other DNA repair pathways, including homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Abnormal expression or mutation of FEN1 in cells can cause a series of pathological responses, leading to various diseases, including cancers. Moreover, overexpression of FEN1 contributes to drug resistance in several types of cancers. All this supports the hypothesis that FEN1 could be a therapeutic target for cancer treatment. Targeting FEN1 has been verified as an effective strategy in mono or combined treatment of cancer. Small-molecule compounds targeting FEN1 have also been developed and detected in cancer regression. In this review, we summarize the recent development of small-molecule inhibitors targeting FEN1 in recent years, thereby expanding their therapeutic potential and application.

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“…The high expression of DOT1-like histone lysine methyltransferase (DOT1L) could promote ovarian cancer cell growth by regulating apoptotic and metabolic pathways, affecting patient prognosis ( Chava et al, 2021 ). In a clinical cohort, flap structure-specific endonuclease 1 (FEN1) is identified as a key molecule in DNA repair, and FEN1 overexpression is associated with poor survival after platinum chemotherapy of ovarian cancer patients ( Mesquita et al, 2021 ). Furthermore, multiple gene-based signatures were also identified for predicting patient survival.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Recurrence Gene Signature for Ovarian Cancer Prognosis by Integrating Single-Cell RNA Sequencing and Bulk Expression Datasets

et al. 2022

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Ovarian cancer is one of the most common gynecological malignancies in women, with a poor prognosis and high mortality. With the expansion of single-cell RNA sequencing technologies, the inner biological mechanism involved in tumor recurrence should be explored at the single-cell level, and novel prognostic signatures derived from recurrence events were urgently identified. In this study, we identified recurrence-related genes for ovarian cancer by integrating two Gene Expression Omnibus datasets, including an ovarian cancer single-cell RNA sequencing dataset (GSE146026) and a bulk expression dataset (GSE44104). Based on these recurrence genes, we further utilized the merged expression dataset containing a total of 524 ovarian cancer samples to identify prognostic signatures and constructed a 13-gene risk model, named RMGS (recurrence marker gene signature). Based on the RMGS score, the samples were stratified into high-risk and low-risk groups, and these two groups displayed significant survival difference in two independent validation cohorts including The Cancer Genome Atlas (TCGA). Also, the RMGS score remained significantly independent in multivariate analysis after adjusting for clinical factors, including the tumor grade and stage. Furthermore, there existed close associations between the RMGS score and immune characterizations, including checkpoint inhibition, EMT signature, and T-cell infiltration. Finally, the associations between RMGS scores and molecular subtypes revealed that samples with mesenchymal subtypes displayed higher RMGS scores. In the meanwhile, the genomics characterization from these two risk groups was also identified. In conclusion, the recurrence-related RMGS model we identified could provide a new understanding of ovarian cancer prognosis at the single-cell level and offer a reference for therapy decisions for patient treatment.

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FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Cited by 14 publications

References 47 publications

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

Identification of a Recurrence Gene Signature for Ovarian Cancer Prognosis by Integrating Single-Cell RNA Sequencing and Bulk Expression Datasets

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