Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients DOI Creative Commons

Kentaro Sugino,

Ryo Tamura, Hirofumi Nakaoka

и другие.

Scientific Reports, Год журнала: 2019, Номер 9(1)

Опубликована: Ноя. 28, 2019

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes major histological types ovarian cancer. performed targeted sequencing to assess 16 HR-associated 4 mismatch repair (MMR) among 207 cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell (CCC), 39 endometrioid (EC), 13 mucinous (MC), 6 low-grade (LGSC)). Germline or were detected 44% HGSC, 28% CCC, 23% EC, 16% MC, 17% LGSC patients. The profile gene was remarkably different each type. BRCA1/2 frequently HGSC rarely observed MC ATM mutation more CCC (9%) EC (18%) than (4%). There a positive correlation between MMR (p = 0.0072). Our findings might be useful selection that should treated with PARP inhibitors.

Язык: Английский

Inherited DNA-Repair Defects in Colorectal Cancer DOI Creative Commons
Saud H. AlDubayan, Marios Giannakis,

Nathanael D. Moore

и другие.

The American Journal of Human Genetics, Год журнала: 2018, Номер 102(3), С. 401 - 414

Опубликована: Фев. 22, 2018

Язык: Английский

Процитировано

96
ATM-Deficient Cancers Provide New Opportunities for Precision Oncology DOI Open Access

Nicholas Jette,

Mehul Kumar,

Suraj Radhamani

и другие.

Cancers, Год журнала: 2020, Номер 12(3), С. 687 - 687

Опубликована: Март 14, 2020

Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations breast and ovarian cancer susceptibility genes BRCA1 BRCA2, with many more potential applications under study clinical trials. Here, we discuss for extending PARP inhibitor therapies to tumours deficiencies DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that inhibition alone is cytostatic but not cytotoxic ATM-deficient cells combination a an ATR (ATM, Rad3-related) required induce cell death.

Язык: Английский

Процитировано

94
IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors DOI Open Access
Remco J. Molenaar, Tomas Radivoyevitch, Yasunobu Nagata

и другие.

Clinical Cancer Research, Год журнала: 2018, Номер 24(7), С. 1705 - 1715

Опубликована: Янв. 16, 2018

Abstract Purpose: Somatic mutations in IDH1/2 occur approximately 20% of patients with myeloid neoplasms, including acute leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates increased DNA damage and improved responses to chemo/radiotherapy PARP inhibitors solid tumor cells. Whether this also holds true for AML is not known. Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT, IDH1/2WT cells were analyzed daunorubicin, ionizing radiation, inhibitors. Results: caused sensitization irradiation, the olaparib talazoparib protected against these treatments. Combined treatment a inhibitor daunorubicin had an additive effect on killing We provide evidence that therapy sensitivity was by D2HG-mediated downregulation expression response gene ATM altered redox due metabolic alterations Conclusions: are sensitive as monotherapy but especially when combined DNA-damaging agent, such whereas concomitant administration during cytotoxic decrease efficacy both agents AML. These results advocate favor clinical trials either or combination Clin Cancer Res; 24(7); 1705–15. ©2018 AACR.

Язык: Английский

Процитировано

92
ATM Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer DOI Open Access

Shahrzad Rafiei,

Kenyon Fitzpatrick,

David Liu

и другие.

Cancer Research, Год журнала: 2020, Номер 80(11), С. 2094 - 2100

Опубликована: Март 3, 2020

Abstract Alterations in DNA damage response (DDR) genes are common advanced prostate tumors and associated with unique genomic clinical features. ATM is a DDR kinase that has central role coordinating repair cell-cycle following damage, alterations present approximately 5% of tumors. Recently, inhibitors PARP have demonstrated activity harboring gene alterations, particularly BRCA1/2 alterations. However, the beyond mediating inhibitor sensitivity poorly understood. To define loss tumor function to DDR-directed agents, we created series ATM-deficient preclinical cancer models tested impact on therapeutic sensitivities. altered signaling, but did not directly homologous recombination function. Furthermore, significantly inhibition robustly sensitized related ATR. These results important implications for planned ongoing trials suggest patients may be more likely benefit from ATR than therapy. Significance: occurs subset This study shows deleting does increase sensitize inhibition. See commentary by Setton Powell, p. 2085

Язык: Английский

Процитировано

91
The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer DOI Creative Commons
Gianluca Mauri, Sabrina Arena, Salvatore Siena

и другие.

Annals of Oncology, Год журнала: 2020, Номер 31(9), С. 1135 - 1147

Опубликована: Июнь 5, 2020

Язык: Английский

Процитировано

66
DNA damage response and repair in colorectal cancer: Defects, regulation and therapeutic implications DOI
Mohammad Mirza‐Aghazadeh‐Attari, Saber Ghazizadeh Darband, Mojtaba Kaviani

и другие.

DNA repair, Год журнала: 2018, Номер 69, С. 34 - 52

Опубликована: Июль 18, 2018

Язык: Английский

Процитировано

65
Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer DOI Creative Commons

Dong-Hyeon Ha,

Ahrum Min,

Seongyeong Kim

и другие.

Scientific Reports, Год журнала: 2020, Номер 10(1)

Опубликована: Июнь 18, 2020

Due to its regulation of CDK1/2 phosphorylation, WEE1 plays essentially roles in the regulations G2/M checkpoint and DNA damage response (DDR). inhibition can increase genomic instability by inducing replication stress inactivation, which result increased cellular sensitivity damaging agents. We considered an induced might be used augment effects drugs targeting repair protein. Typically, PARP inhibitors are effective germline BRCA 1/2 mutated breast ovarian cancer, but their applicabilities triple-negative cancer (TNBC) limited. This study was conducted investigate anti-tumor inhibitor, AZD1775, mechanism responsible for potentiation olaparib (a inhibitor) via modulation DDR TNBC cells. Our results suggest that AZD1775 could broaden application range provide a rationale clinical trial combined therapy.

Язык: Английский

Процитировано

60
DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy DOI
Larissa Costa de Almeida, Felipe A. Calil, João Agostinho Machado‐Neto

и другие.

Cancer Genetics, Год журнала: 2020, Номер 252-253, С. 6 - 24

Опубликована: Дек. 9, 2020

Язык: Английский

Процитировано

60
Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer DOI Open Access
Fabio Catalano, Roberto Borea, Silvia Puglisi

и другие.

Cancers, Год журнала: 2022, Номер 14(6), С. 1388 - 1388

Опубликована: Март 9, 2022

Major advances have been made in CRC treatment recent years, especially molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments their prognosis remains poor. The landscape DNA damage response (DDR) alterations is emerging as novel target for different types. PARP inhibitors approved the ovarian, breast, pancreatic, prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on role HRD showed that genes, either germline somatic, are carried by up to 15-20% CRCs. However, still widely unknown, few data about clinical impact available, patients. In this review, we report preclinical currently available DDR CRC. We also emphasize predictive mutations platinum-based chemotherapy potential inhibitors. More trials required better understand therapeutic opportunities with

Язык: Английский

Процитировано

35
Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma DOI Creative Commons
Yuewei Xu, Sarah Spear, Yurui Ma

и другие.

Cell Reports, Год журнала: 2023, Номер 42(10), С. 113307 - 113307

Опубликована: Окт. 1, 2023

Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients BRCA1/2 mutations. However, acquired drug resistance relapse major challenge. Indisulam (E7070) has been identified as molecular glue that brings together splicing factor RBM39 DCAF15 E3 ubiquitin ligase resulting polyubiquitination, degradation, subsequent RNA defects. this work, we demonstrate loss induces defects key DNA damage repair genes cancer, leading to increased sensitivity cisplatin various PARP inhibitors. The addition indisulam also improved olaparib response mice bearing inhibitor-resistant tumors. These findings combining degraders promising approach improve inhibitor HGSC.

Язык: Английский

Процитировано

18