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TTK activates ATR through RPA2 phosphorylation to promote olaparib resistance in ovarian cancer.
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- Additional Information
- Source:
Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE
- Publication Information:
Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]-
- Subject Terms:
- Abstract:
Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: All methods in this study were performed in accordance with the relevant guidelines and regulations. Ethics Committee at Qilu Hospital of Shandong University approved the study. The tumor formation assay was approved by the Shandong University Animal Care and Use Committee. Informed consent: All authors of the manuscript agree to article's publication.
Resistance to poly(ADP‒ribose) polymerase inhibitors (PARPis) remains a significant challenge in ovarian cancer (OC) treatment. TTK protein kinase (TTK) has been implicated in cisplatin resistance in OC, but its role in PARPi resistance remains unclear. In this research, we found that TTK inhibition overcome olaparib resistance in HR-proficient OC cells, whereas TTK promotes olaparib resistance in HR-deficient OC cells. Mechanistically, TTK directly interacts with RPA2, facilitating phosphorylation of its S33 residue to activate the ATR signaling pathway. Knocking down RPA2 increased olaparib sensitivity in OC cells. Additionally, TTK-mediated resistance to olaparib through the RPA2/ATR signaling pathway was confirmed via both in vitro and in vivo models. In conclusion, TTK inhibition overcomes olaparib resistance in HR-proficient OC cells, in part by suppressing RPA2-S33 phosphorylation and attenuating ATR signaling. TTK inhibitors offer a promising strategy to increase the therapeutic efficacy of PARPis in OC patients.
(© 2025. The Author(s).)
- References:
Int J Mol Sci. 2020 Dec 19;21(24):. (PMID: 33352723)
Annu Rev Biochem. 2012;81:561-85. (PMID: 22482908)
Nat Struct Mol Biol. 2010 Mar;17(3):365-72. (PMID: 20154705)
J Biol Chem. 1997 Sep 19;272(38):23896-904. (PMID: 9295339)
Cell Rep. 2013 May 30;3(5):1651-62. (PMID: 23684611)
Ann Oncol. 2016 Apr;27 Suppl 1:i58-i62. (PMID: 27141074)
Cell Death Dis. 2021 Dec 7;12(12):1135. (PMID: 34876569)
Carcinogenesis. 2010 Jun;31(6):994-1002. (PMID: 20130019)
J Biol Chem. 2005 Mar 4;280(9):7748-57. (PMID: 15618221)
Curr Biol. 2012 Nov 20;22(22):R966-80. (PMID: 23174302)
Curr Biol. 2005 Jan 26;15(2):160-5. (PMID: 15668173)
PLoS One. 2017 Apr 5;12(4):e0174863. (PMID: 28380042)
Gynecol Oncol. 2018 Jun;149(3):575-584. (PMID: 29567272)
Biomed Pharmacother. 2016 Oct;83:898-904. (PMID: 27522003)
Biochemistry. 2005 Jun 14;44(23):8428-37. (PMID: 15938632)
Biochem J. 2005 Nov 1;391(Pt 3):473-80. (PMID: 15929725)
Nucleic Acids Res. 2016 Feb 18;44(3):1133-50. (PMID: 26531827)
Oncogene. 2009 Mar 12;28(10):1366-78. (PMID: 19151762)
Trends Cancer. 2021 Dec;7(12):1102-1118. (PMID: 34563478)
Nat Rev Clin Oncol. 2021 Dec;18(12):773-791. (PMID: 34285417)
Cell Death Dis. 2022 Mar 24;13(3):263. (PMID: 35332131)
Biochem Biophys Res Commun. 2021 Apr 23;550:84-91. (PMID: 33689884)
Ann Oncol. 2015 Oct;26(10):2180-92. (PMID: 26153498)
Med Oncol. 2019 Nov 13;37(1):5. (PMID: 31720873)
J Clin Invest. 2020 Feb 3;130(2):958-973. (PMID: 31961339)
PLoS One. 2014 Jun 06;9(6):e97739. (PMID: 24905462)
J Natl Compr Canc Netw. 2024 Feb;22(1):43-69. (PMID: 38394770)
Int J Clin Exp Pathol. 2018 Oct 01;11(10):4854-4861. (PMID: 31949560)
Nat Rev Cancer. 2011 Sep 23;11(10):719-25. (PMID: 21941283)
Cell Death Discov. 2025 Jan 28;11(1):29. (PMID: 39875359)
Cell Death Discov. 2021 Sep 22;7(1):259. (PMID: 34552062)
Cancer Res. 2004 Oct 1;64(19):7139-43. (PMID: 15466211)
J Biol Chem. 1997 May 9;272(19):12634-41. (PMID: 9139719)
J Biol Chem. 2007 Dec 7;282(49):35910-23. (PMID: 17928296)
Semin Cell Dev Biol. 2019 Feb;86:112-120. (PMID: 29665433)
Clin Cancer Res. 2023 Aug 1;29(15):2800-2807. (PMID: 37097611)
Exp Cell Res. 2019 Dec 1;385(1):111669. (PMID: 31605696)
J Exp Clin Cancer Res. 2022 Dec 21;41(1):355. (PMID: 36539830)
Cancers (Basel). 2022 Apr 28;14(9):. (PMID: 35565334)
J Biol Chem. 2005 Sep 23;280(38):32775-83. (PMID: 16006651)
Head Neck. 2010 May;32(5):636-45. (PMID: 19787780)
Oncotarget. 2015 Oct 27;6(33):34309-20. (PMID: 26418879)
Cancer Res. 2018 Oct 1;78(19):5561-5573. (PMID: 30072396)
FEBS Open Bio. 2020 Aug;10(8):1542-1549. (PMID: 32530571)
Trends Cell Biol. 2019 Oct;29(10):820-834. (PMID: 31421928)
Mol Cancer. 2020 Jun 20;19(1):107. (PMID: 32563252)
J Mol Biol. 2007 Oct 12;373(1):38-47. (PMID: 17765923)
Gynecol Oncol. 2016 Oct;143(1):143-151. (PMID: 27444036)
Mol Cancer Res. 2015 May;13(5):852-62. (PMID: 25722303)
- Grant Information:
ZR2021QH020 Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation); ZR2023QH306 Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation); ZR2024MH293 Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation); 82303896 National Natural Science Foundation of China (National Science Foundation of China)
- Accession Number:
WOH1JD9AR8 (olaparib)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
0 (Piperazines)
0 (Phthalazines)
EC 2.7.11.1 (ATR protein, human)
0 (Poly(ADP-ribose) Polymerase Inhibitors)
EC 2.7.7.7 (RPA2 protein, human)
0 (Replication Protein A)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
0 (Cell Cycle Proteins)
- Publication Date:
Date Created: 20250705 Date Completed: 20250705 Latest Revision: 20250708
- Publication Date:
20250708
- Accession Number:
PMC12228772
- Accession Number:
10.1038/s42003-025-08444-7
- Accession Number:
40617868
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