Targeting the DNA repair pathway for breast cancer therapy: Beyond the molecular subtypes

Qu, Yuting; Qin, Sisi; Yang, Zhihui; Li, Zhuolin; Liang, Qinhao; Long, Ting; Wang, Weiyun; Zeng, Dan; Zhao, Qing; Dai, Zehua; Ni, Qing; Zhao, Fei; Kim, Wootae; Hou, Jing

doi:10.1016/j.biopha.2023.115877

Cited by 2 publications

(3 citation statements)

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“…Defective DDR and the accumulation of DNA damage are established hallmarks of tumorigenesis and its progression to aggressive stages. Several FDA-approved PARP1 inhibitors (Olaparib, Niraparib, Rucaparib, Talazoparib, Fuzuloparib, and Pamiparib), although limited by the development of resistance, are used for treating a wide range of cancers [ 44 , 45 , 46 , 47 , 48 ]. Molecular docking analyses have shown earlier that Mortaparib Mild has the capability of interacting directly with the catalytic binding domain of PARP1 [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

Wadhwa,

Yang,

Meidinna

et al. 2024

Cancers

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Mortalin, a member of the Hsp70 family of proteins, is commonly enriched in many types of cancers. It promotes carcinogenesis and metastasis in multiple ways of which the inactivation of the tumor suppressor activity of p53 has been firmly established. The downregulation of mortalin and/or disruption of mortalin–p53 interactions by small molecules has earlier been shown to activate p53 function yielding growth arrest/apoptosis in cancer cells. Mortaparibs (Mortaparib, MortaparibPlus, and MortaparibMild) are chemical inhibitors of mortalin isolated by cell-based two-way screening involving (i) a shift in the mortalin staining pattern from perinuclear (characteristics of cancer cells) to pancytoplasmic (characteristics of normal cells) and (ii) the nuclear enrichment of p53. They have similar structures and also cause the inhibition of PARP1 and hence were named Mortaparibs. In the present study, we report the anticancer and anti-metastasis activity of MortaparibMild (4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine) in p53-null cells. By extensive molecular analyses of cell proliferation, growth arrest, and apoptosis pathways, we demonstrate that although it causes relatively weaker cytotoxicity compared to Mortaparib and MortaparibPlus, its lower concentrations were equally potent to inhibit cell migration. We developed combinations (called MortaparibMix-AP, MortaparibMix-AM, and MortaparibMix-AS) consisting of different ratios of three Mortaparibs for specifically enhancing their anti-proliferation, anti-migration, and antistress activities, respectively. Based on the molecular analyses of control and treated cells, we suggest that the three Mortaparibs and their mixtures may be considered for further laboratory and clinical studies validating their use for the treatment of cancer as well as prevention of its relapse and metastasis.

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Section: Discussionmentioning

confidence: 99%

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

Wadhwa,

Yang,

Meidinna

et al. 2024

Cancers

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“…This study enrolled 9 patients with gBRCA wild type who had undergone at least one prior treatment. Prexasertib demonstrated modest clinical efficacy in BRCA-wild type TNBC, with one patient experiencing a partial response (ORR 11.1%) and four patients achieving stable disease [84].…”

Section: Chek1/2 Inhibitorsmentioning

confidence: 99%

“…One promising therapeutic strategy involves combining prexasertib with PARPi, since it has been shown that when olaparib is combined with a CHEK1 inhibitor, it diminishes HR efficiency and reduces replication fork stability [ 85 ].…”

Section: Current Development Of Other Dna Damage-targeted Treatments ...mentioning

confidence: 99%

DNA damage targeted therapy for advanced breast cancer

Patel,

Casimiro,

Abreu

et al. 2024

Exploration of Targeted Anti-Tumor Therapy

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Breast cancer (BC) is the most prevalent malignancy affecting women worldwide, including Portugal. While the majority of BC cases are sporadic, hereditary forms account for 5-10% of cases. The most common inherited mutations associated with BC are germline mutations in the BReast CAncer (BRCA) 1/2 gene (gBRCA1/2). They are found in approximately 5-6% of BC patients and are inherited in an autosomal dominant manner, primarily affecting younger women. Pathogenic variants within BRCA1/2 genes elevate the risk of both breast and ovarian cancers and give rise to distinct clinical phenotypes. BRCA proteins play a key role in maintaining genome integrity by facilitating the repair of double-strand breaks through the homologous recombination (HR) pathway. Therefore, any mutation that impairs the function of BRCA proteins can result in the accumulation of DNA damage, genomic instability, and potentially contribute to cancer development and progression. Testing for gBRCA1/2 status is relevant for treatment planning, as it can provide insights into the likely response to therapy involving platinum-based chemotherapy and poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi). The aim of this review was to investigate the impact of HR deficiency in BC, focusing on BRCA mutations and their impact on the modulation of responses to platinum and PARPi therapy, and to share the experience of Unidade Local de Saúde Santa Maria in the management of metastatic BC patients with DNA damage targeted therapy, including those with the Portuguese c.156_157insAlu BRCA2 founder mutation.

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Targeting the DNA repair pathway for breast cancer therapy: Beyond the molecular subtypes

Cited by 2 publications

References 58 publications

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

DNA damage targeted therapy for advanced breast cancer

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