Advances in therapeutic targeting of the DNA damage response in cancer

Desai, Amar; Yan, Yan; Gerson, Stanton L.

doi:10.1016/j.dnarep.2018.04.004

Cited by 51 publications

(42 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Exogenous and endogenous DNA damage contribute to germline or somatic DNA repair deficiencies in cancer [28]. The identification of somatic mutations involving DDR may help in targeted therapy with a genomic approach [29,30]. We identified somatic mutations in DNA repair pathways of single-strand breaks (SSBs) and double-strand breaks (DSBs).…”

Section: Potential Therapeutic Targeting From Mutations Of the Ddrmentioning

confidence: 99%

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan

Jou

et al. 2020

Cancers

View full text Add to dashboard Cite

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

show abstract

Section: Potential Therapeutic Targeting From Mutations Of the Ddrmentioning

confidence: 99%

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan

Jou

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…Many established therapeutic modalities, such as radio-and chemotherapy that attack cancer cell DNA are in clinical use but provide limited benefit to cancer patients. This is due, at least in part, to the competence of tumor cells to deal with DNA damage (2).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models

Zenke

Zimmermann

Sirrenberg

et al. 2020

Molecular Cancer Therapeutics

109

View full text Add to dashboard Cite

Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials.

show abstract

“…Moreover, inhibiting ATR in Pol η-depleted or deficient cells undergoing replicative stress resulted in synthetic lethality, suggesting a possible therapeutic option. Importantly, ATR and Chk1 inhibitors are a promising avenue of drug therapy with both currently undergoing clinical trials [ 231 ]. Thus, targeting specific tumors based on expression of specialized DNA polymerases to generate synthetic lethality undergoing “oncogene addiction” may be a viable therapeutic option in the future.…”

Section: Perspectivementioning

confidence: 99%

Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress

Tsao

Eckert

2018

IJMS

View full text Add to dashboard Cite

Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures formed by repetitive sequences, for example within chromosomal fragile sites and telomeres, which inhibit DNA replication under endogenous stress conditions. Oncogene activation alters DNA replication dynamics and creates oncogenic replication stress, resulting in persistent activation of the DNA damage and replication stress responses, cell cycle arrest, and cell death. The response to oncogenic replication stress is highly complex and must be tightly regulated to prevent mutations and tumorigenesis. In this review, we summarize types of known DiToRS and the experimental evidence supporting replication inhibition, with a focus on the specialized DNA polymerases utilized to cope with these obstacles. In addition, we discuss different causes of oncogenic replication stress and its impact on DiToRS stability. We highlight recent findings regarding the regulation of DNA polymerases during oncogenic replication stress and the implications for cancer development.

show abstract

Advances in therapeutic targeting of the DNA damage response in cancer

Cited by 51 publications

References 58 publications

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models

Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress

Contact Info

Product

Resources

About