MRE11 as a molecular signature and therapeutic target for cancer treatment with radiotherapy

Yy, Wang; Hung, Amos C.; Lo, Steven; Hsieh, Ya‐Ching; Yuan, Shyng‐Shiou F.

doi:10.1016/j.canlet.2021.05.013

Cited by 15 publications

(12 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MRE11 also has endonuclease and exonuclease activities residing in the phosphodiesterase domain. These nuclease activities are crucial for the pathway choice of HR and NHEJ (131). Cancer cells rely on DNA repair for survival during cancer therapies, and thus MRE11 might be a promising synergistic therapeutic target.…”

Section: Mre11mentioning

confidence: 99%

“…OBP-301, with the insertion of the human telomerase reverse transcriptase (hTERT) promotor, also showed reduced MRE11 expression and thus enhanced radiosensitivity of lung cancer cells (137). Therefore, MRE11 inhibitors are clinically significant for enhancing radiosensitivity, and several clinical trials investigating their potential are ongoing (131).…”

Section: Mre11mentioning

confidence: 99%

See 1 more Smart Citation

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

show abstract

Section: Mre11mentioning

confidence: 99%

Section: Mre11mentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Here, we observed that ANKHD1 or MALAT1 silencing inhibited the DDR by decreasing the transcriptional activity of YAP1. AKT promotes DSB repair by upregulating MRE11 expression [ 36 ], and the activation of AKT is crucial in YAP1-mediated radioresistance [ 23 ]. In accordance with these studies, we showed that ANKHD1 increased the activation of AKT in a YAP1-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

The feedback loop of ANKHD1/lncRNA MALAT1/YAP1 strengthens the radioresistance of CRC by activating YAP1/AKT signaling

Yao

Zhao

et al. 2022

Cell Death Dis

View full text Add to dashboard Cite

Innate radioresistance substantially limits the effectiveness of radiotherapy for colorectal cancer (CRC); thus, a strategy to enhance the radiosensitivity of CRC is urgently needed. Herein, we reported that ankyrin repeat and KH domain containing 1 (ANKHD1) serves as a key regulator of radioresistance in CRC. ANKHD1 was highly expressed in CRC tissues and was highly correlated with Yes-associated protein 1 (YAP1) in CRC. Our results first revealed that ANKHD1 knockdown could increase the radiosensitivity of CRC by regulating DNA-damage repair, both in vitro and in vivo. Furthermore, the interactive regulation between ANKHD1 or YAP1 and lncRNA MALAT1 was revealed by RIP and RNA pull-down assays. Moreover, our results also demonstrated that MALAT1 silencing can radiosensitize CRC cells to IR through YAP1/AKT axis, similar to ANKHD1 silencing. Taken together, we report a feedback loop of ANKHD1/MALAT1/YAP1 that synergistically promotes the transcriptional coactivation of YAP1 and in turn enhances the radioresistance of CRC by regulating DNA-damage repair, probably via the YAP1/AKT axis. Our results suggested that targeting the YAP1/AKT axis downstream of ANKHD1/MALAT1/YAP1 may enhance the radiosensitivity of CRC.

show abstract

“…The high-level expression of MRN complex is associated with chemo- and radio-resistance in breast cancer, glioblastoma and NSCLC as well as correlated with worse disease-free (DFS) and poor overall survival (OS) in rectal, prostate, gastric and NSCLC patients. However, the consequences of defects and/or altered expression level of MRN complex are still controversial with respect to its dual roles in tumorigenesis and prognosis ( 125 – 128 ).…”

Section: Inhibitors Targeting Hdr Pathwaymentioning

confidence: 99%

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

et al. 2022

View full text Add to dashboard Cite

The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many cancer subtypes and can promote de novo carcinogenesis, genomic instability, and ensuing resistance to current cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of DSB repair including Ku70/80, Artemis, DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact cancer treatment.

show abstract

MRE11 as a molecular signature and therapeutic target for cancer treatment with radiotherapy

Cited by 15 publications

References 123 publications

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

The feedback loop of ANKHD1/lncRNA MALAT1/YAP1 strengthens the radioresistance of CRC by activating YAP1/AKT signaling

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

Contact Info

Product

Resources

About