Regulation and pharmacological targeting of RAD51 in cancer

Grundy, McKenzie K; Buckanovich, Ronald J.; Bernstein, Kara A.

doi:10.1093/narcan/zcaa024

Cited by 53 publications

(63 citation statements)

References 187 publications

(261 reference statements)

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“…Therefore, targeting RAD51 may increase the susceptibility of tumors to chemo and radiotherapy. Indeed, several small-molecule inhibitors of RAD51 have been developed and were shown to sensitize cancer cells to chemotherapy and [ 35 , 52 , 69 , 70 ]. Here, we identified a new series of HR inhibitors, B02-iso, that bind to RAD51.…”

Section: Discussionmentioning

confidence: 99%

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

Shkundina

Gall²,

Dick

et al. 2021

Genes

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Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. Here, using a medicinal chemistry approach, we aimed to improve the potency of B02. We identified the B02 analog, B02-isomer, which inhibits HR in human cells with significantly higher efficiency. We also show that B02-iso sensitizes triple-negative breast cancer MDA-MB-231 cells to the PARP inhibitor (PARPi) olaparib.

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Section: Discussionmentioning

confidence: 99%

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

Shkundina

Gall²,

Dick

et al. 2021

Genes

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“…1A,1B, Additional file 1: Figure S4B, 4C). Although RAD51B mutations have been reported in a few cases in breast cancer, their pathogenic significance remains controversial 29 . To the best of our knowledge, there have been no reports on homozygous deletion in RAD51B .…”

Section: Resultsmentioning

confidence: 99%

The utility of homologous recombination deficiency biomarkers across cancer types

Takamatsu

Brown

Yamaguchi

et al. 2021

Preprint

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Background: Genomic alterations in BRCA1/2 and genomic scar signatures are associated with homologous recombination DNA repair deficiency (HRD) and serve as therapeutic biomarkers for platinum and PARP inhibitors in breast and ovarian cancers. However, the clinical significance of these biomarkers in other homologous recombination repair-related genes or other cancer types is not fully understood. Results: We analyzed the datasets of all solid cancers from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and found that the association between biallelic alterations in the homologous recombination pathway genes and genomic scar signatures differed greatly depending on gender and the presence of somatic TP53 mutation. Additionally, HRD cases identified by a combination of these indicators showed higher sensitivity to DNA-damaging drugs than non-HRD cases both in clinical samples and cell lines. Conclusion: Our work provides novel proof of the utility of HRD analysis for all cancer types and will improve the precision and efficacy of chemotherapy selection in clinical oncology.

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“…Most of these mutations were classified as variants of unknown significance, but some were functionally characterized (F86L, D149N, Q268P, Q272L) and determined to affect one of the functions of RAD51 (ATPase activity, DNA binding, strand exchange activity and/or thermal stability) ( 28 ). However, the HR process itself was not evaluated in cells (for review see ( 29 )). All of the mutations were found in breast cancers, with the exceptions of Q268P (lung cancer) and Q272L (kidney cancer).…”

Section: Mutation and Downregulation Of Hr Genes In Human Pathologies: The Rad51 Paradoxmentioning

confidence: 99%

“…In contrast with the general pattern of HR-inactivating mutations promoting breast cancer, RAD51 overexpression is associated with poor prognosis ( https://www.proteinatlas.org ). Therefore, RAD51 is a pharmacological target, and RAD51 inhibitors are being developed ( 29 ).…”

Section: Mutation and Downregulation Of Hr Genes In Human Pathologies: The Rad51 Paradoxmentioning

confidence: 99%

Homologous recombination, cancer and the ‘RAD51 paradox’

2021

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Genetic instability is a hallmark of cancer cells. Homologous recombination (HR) plays key roles in genome stability and variability due to its roles in DNA double-strand break and interstrand crosslink repair, and in the protection and resumption of arrested replication forks. HR deficiency leads to genetic instability, and, as expected, many HR genes are downregulated in cancer cells. The link between HR deficiency and cancer predisposition is exemplified by familial breast and ovarian cancers and by some subgroups of Fanconi anaemia syndromes. Surprisingly, although RAD51 plays a pivotal role in HR, i.e., homology search and in strand exchange with a homologous DNA partner, almost no inactivating mutations of RAD51 have been associated with cancer predisposition; on the contrary, overexpression of RAD51 is associated with a poor prognosis in different types of tumours. Taken together, these data highlight the fact that RAD51 differs from its HR partners with regard to cancer susceptibility and expose what we call the ‘RAD51 paradox’. Here, we catalogue the dysregulations of HR genes in human pathologies, including cancer and Fanconi anaemia or congenital mirror movement syndromes, and we discuss the RAD51 paradox.

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Regulation and pharmacological targeting of RAD51 in cancer

Cited by 53 publications

References 187 publications

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

The utility of homologous recombination deficiency biomarkers across cancer types

Homologous recombination, cancer and the ‘RAD51 paradox’

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