scholarly journals Identifying and Overcoming Mechanisms of PARP Inhibitor Resistance in Homologous Recombination Repair-Deficient and Repair-Proficient High Grade Serous Ovarian Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1503
Author(s):  
Miriam K. Gomez ◽  
Giuditta Illuzzi ◽  
Carlota Colomer ◽  
Michael Churchman ◽  
Robert L. Hollis ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Strand Breaks ◽  
G2 Checkpoint ◽  
Recombination Repair ◽  
Wee1 Kinase ◽  
Inhibitor Resistance

High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib.

scholarly journals C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jiahong Tan ◽  
Xu Zheng ◽  
Mengchen Li ◽  
Fei Ye ◽  
Chunyan Song ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitors ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Enhancer Binding Protein ◽  
Recombination Repair ◽  
Inhibitor Resistance

AbstractPARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.

scholarly journals RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer

2018 ◽  
Vol 29 (5) ◽  
pp. 1203-1210 ◽  
Author(s):  
C. Cruz ◽  
M. Castroviejo-Bermejo ◽  
S. Gutiérrez-Enríquez ◽  
A. Llop-Guevara ◽  
Y.H. Ibrahim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Inhibitor Resistance

scholarly journals TP53mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer

2015 ◽  
Vol 43 (14) ◽  
pp. 6945-6958 ◽  
Author(s):  
Jeremy Chien ◽  
Hugues Sicotte ◽  
Jian-Bing Fan ◽  
Sean Humphray ◽  
Julie M. Cunningham ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Early Stage ◽  
Homologous Recombination Repair ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Recombination Repair

scholarly journals REV7/FANCV Binds to CHAMP1 and Promotes Homologous Recombination Repair

2021 ◽  
Author(s):  
Feng Li ◽  
Prabha Sarangi ◽  
Hanrong Feng ◽  
Lisa Moreau ◽  
Huy Nguyen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Dna Double Strand Breaks ◽  
Critical Determinant ◽  
Strand Breaks ◽  
Positive Regulator ◽  
Recombination Repair ◽  
Nhej Repair ◽  
Inhibitor Resistance

A critical determinant of DNA repair pathway choice is the HORMA protein REV7, a small abundant adaptor which binds to various DNA repair proteins through its C-terminal seatbelt domain. The REV7 seatbelt binds to the REV3 polymerase to form the Polymerase ζ complex, a positive regulator of translesion synthesis (TLS) repair. Alternatively, the REV7 seatbelt binds to SHLD3 in the Shieldin complex, a positive regulator of NHEJ repair. Recent studies have identified another novel REV7 seatbelt-binding protein, CHAMP1 (Chromosome Alignment-Maintaining Phosphoprotein, though its role in DNA repair is unknown. Here, we show that the REV7-CHAMP1 complex promotes homologous recombination (HR) repair by sequestering REV7 from the Shieldin complex. CHAMP1 competes directly with the SHLD3 subunit of the Shieldin complex for a limited pool of C-REV7, thereby inhibiting the REV7-mediated recruitment of the SHLD2 and SHLD1 effector subunits to DNA double strand breaks. CHAMP1 thereby channels DNA repair away from error-prone NHEJ and towards the competing error-free HR pathway. Similarly, CHAMP1 competes with the REV3 component of the POLζ complex, thereby reducing the level of mutagenic TLS repair. CHAMP1 interacts with POGZ in a heterochromatin complex further promoting HR repair. Importantly, in human tumors, CHAMP1 overexpression promotes HR, confers PARP inhibitor resistance, and correlates with poor prognosis. Thus, by binding to either REV3, SHLD3, or CHAMP1 through its seatbelt, the REV7 protein can promote either TLS repair, NHEJ repair, or HR repair respectively.

scholarly journals EML4-ALK, a potential therapeutic target that responds to alectinib in ovarian cancer

2020 ◽  
Vol 50 (12) ◽  
pp. 1470-1474
Author(s):  
Beina Hui ◽  
Jingping Zhang ◽  
Xiaobo Shi ◽  
Fangfang Xing ◽  
Yang W Shao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Kinase Gene ◽  
Anaplastic Lymphoma Kinase Inhibitor ◽  
Anaplastic Lymphoma

Abstract Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.

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