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Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer

Sahin, Irem Durmaz LU ; Jönsson, Jenny Maria LU and Hedenfalk, Ingrid LU orcid (2019) In Oncotarget 10(65). p.6981-6996
Abstract

High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib,... (More)

High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Apoptosis, C-Met, HGSOC, PARP inhibitor
in
Oncotarget
volume
10
issue
65
pages
16 pages
publisher
Impact Journals
external identifiers
  • scopus:85077572876
  • pmid:31857852
ISSN
1949-2553
DOI
10.18632/oncotarget.27363
language
English
LU publication?
yes
id
34d86a72-ca96-4f36-8954-d2c399459b3a
date added to LUP
2020-01-23 14:49:32
date last changed
2024-05-01 04:49:10
@article{34d86a72-ca96-4f36-8954-d2c399459b3a,
  abstract     = {{<p>High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.</p>}},
  author       = {{Sahin, Irem Durmaz and Jönsson, Jenny Maria and Hedenfalk, Ingrid}},
  issn         = {{1949-2553}},
  keywords     = {{Apoptosis; C-Met; HGSOC; PARP inhibitor}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{65}},
  pages        = {{6981--6996}},
  publisher    = {{Impact Journals}},
  series       = {{Oncotarget}},
  title        = {{Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer}},
  url          = {{http://dx.doi.org/10.18632/oncotarget.27363}},
  doi          = {{10.18632/oncotarget.27363}},
  volume       = {{10}},
  year         = {{2019}},
}