PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

Wang, Nannan; Yan, Yang; Da, Jin; Zhang, Zhenan; Shen, Ke; Yang, Jing; Chen, Huanhuan; Zhao, Xinyue; Li, Yang; Lu, Huaiwu

doi:10.3389/fphar.2022.967633

Cited by 17 publications

(15 citation statements)

References 153 publications

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“…Mechanisms contributing to resistance to PARPi in BRCA1 mutated cells are (I) increase in drug efflux, (II) restoration of HR, (III) decreased PARP1 trapping, and (IV) stabilization of stalled DNA replication forks [ 9 , 48 ]. All BRCA1 mutated clones still show residual HR activity, most strongly in the MMC- and PAPR1i-resistant BRCA1 exon-9.2 clone, contributing to the observed resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the involvement of BRCA1 in all the key steps of HR, a loss of BRCA1 can lead to a HR-deficiency (HRD) [ 7 , 8 ]. Several studies showed that overexpression of other involved DNA damage response (DDR) or HR proteins can at least partially compensate for the loss and restore the function of HR [ 9 , 10 ]. A defect in HR is associated with an increased sensitivity to platinum-based chemotherapies and PARP1 inhibitors in a synthetic lethal manner, though not always resulting in improved patient survival [ 5 , 8 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…RS can be counteracted by elevated CHK1 activation, which inhibits the firing of new origins of replication, allowing stalled replication forks to restart [ 19 , 20 , 21 , 22 ]. This may lead to therapy resistance, which was shown to be able to be overcome by CHK1 inhibition in TNBC [ 9 ]. A second pathway to overcome RS is via the Fanconi anemia protein complex, mediated by FANCD2/FANCI.…”

Section: Introductionmentioning

confidence: 99%

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Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance

Classen

Rahlf

Jungwirth

et al. 2022

IJMS

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BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance

Classen

Rahlf

Jungwirth

et al. 2022

IJMS

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“…This has offered a therapeutic vulnerability that has been extensively explored clinically in BRCA1/2 mutant patients but is now also being examined as a viable therapy in tumours with other specific genotypes, including those presenting with ATM , PALB2 , RAD51C , and RAD51D mutations [ 117 ]. As mentioned previously, the major drawback of PARP inhibitors is the rapid onset of acquired resistance which is mediated through multiple mechanisms [ 118 ]. A better understanding of this will lead to novel therapeutic approaches that harness the power of drug targeting PARP enzymes, increasing the repertoire of potential therapeutic targets for CSCs.…”

Section: The Dna Damage Response (Ddr)mentioning

confidence: 99%

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

Gillespie

Ward

Davies

2023

Cancers

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First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.

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“…Ovarian (OC), cervical (CC), and endometrial cancer (EC) are the most common gynecological cancers in the female reproductive system ( 1 , 2 ). OC is the most lethal gynecological malignancy in developed countries ( 3 ), with a 5-year survival rate of ~47% ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Clinical characterization and genomic landscape of gynecological cancers among patients attending a Chinese hospital

Jiang

Liu

et al. 2023

Front. Oncol.

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BackgroundGynecological cancers are the most lethal malignancies among females, most of which are associated with gene mutations. Few studies have compared the differences in the genomic landscape among various types of gynecological cancers. In this study, we evaluated the diversity of mutations in different gynecological cancers.MethodsA total of 184 patients with gynecological cancer, including ovarian, cervical, fallopian tube, and endometrial cancer, were included. Next-generation sequencing was performed to detect the mutations and tumor mutational burden (TMB). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were also conducted.ResultsWe found that 94.57% of patients had at least one mutation, among which single nucleotide variants, insertions and InDels were in the majority. TP53, PIK3CA, PTEN, KRAS, BRCA1, BRCA2, ARID1A, KMT2C, FGFR2, and FGFR3 were the top 10 most frequently mutated genes. Patients with ovarian cancer tended to have higher frequencies of BRCA1 and BRCA2 mutations, and the frequency of germline BRCA1 mutations (18/24, 75.00%) was higher than that of BRCA2 (11/19, 57.89%). A new mutation hotspot in BRCA2 (I770) was firstly discovered among Chinese patients with gynecological cancer. Patients with TP53, PIK3CA, PTEN, and FGFR3 mutations had significantly higher TMB values than those with wild-type genes. A significant cross was discovered between the enriched KEGG pathways of gynecological and breast cancers. GO enrichment revealed that the mutated genes were crucial for the cell cycle, neuronal apoptosis, and DNA repair.ConclusionVarious gynecological cancer types share similarities and differences both in clinical characterization and genomic mutations. Taken together with the results of TMB and enriched pathways, this study provided useful information on the molecular mechanism underlying gynecological cancers and the development of targeted drugs and precision medicine.

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PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

Cited by 17 publications

References 153 publications

Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance

Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

Clinical characterization and genomic landscape of gynecological cancers among patients attending a Chinese hospital

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