Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification
Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown...
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| Veröffentlicht in: | International journal of molecular sciences 2022-09, Vol.23 (18), p.10892 |
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| creator | Gasimli, Khayal Raab, Monika Tahmasbi Rad, Morva Kurunci-Csacsko, Elisabeth Becker, Sven Strebhardt, Klaus Sanhaji, Mourad |
| description | Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist. |
| doi_str_mv | 10.3390/ijms231810892 |
| format | Article |
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High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms231810892</identifier><identifier>PMID: 36142803</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Apoptosis ; BRCA1 protein ; BRCA1 Protein - genetics ; BRCA2 protein ; Breast cancer ; Cancer therapies ; Carboplatin ; Carboplatin - therapeutic use ; Cell cycle ; Cell Cycle Proteins - metabolism ; Cell division ; Chemotherapy ; Cystadenocarcinoma, Serous - drug therapy ; DNA damage ; Female ; Gene expression ; Humans ; K-Ras protein ; Kinases ; Malignancy ; Medical prognosis ; Mutation ; Neoplasm Recurrence, Local - drug therapy ; Neoplasm Recurrence, Local - genetics ; Ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - pathology ; Patients ; Phthalazines - pharmacology ; Point mutation ; Polo-Like Kinase 1 ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use ; Protein Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins p21(ras) - genetics ; Spheroids ; Targeted cancer therapy ; Tumors</subject><ispartof>International journal of molecular sciences, 2022-09, Vol.23 (18), p.10892</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c345t-13c93c4cf82c99c4e5141fb2a05e25aa38426a75853f9e493c72f27c440320b83</citedby><cites>FETCH-LOGICAL-c345t-13c93c4cf82c99c4e5141fb2a05e25aa38426a75853f9e493c72f27c440320b83</cites><orcidid>0000-0001-8202-0694 ; 0000-0003-1874-0341 ; 0000-0003-2173-9763</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502276/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502276/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36142803$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gasimli, Khayal</creatorcontrib><creatorcontrib>Raab, Monika</creatorcontrib><creatorcontrib>Tahmasbi Rad, Morva</creatorcontrib><creatorcontrib>Kurunci-Csacsko, Elisabeth</creatorcontrib><creatorcontrib>Becker, Sven</creatorcontrib><creatorcontrib>Strebhardt, Klaus</creatorcontrib><creatorcontrib>Sanhaji, Mourad</creatorcontrib><title>Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. 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Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.</description><subject>Apoptosis</subject><subject>BRCA1 protein</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA2 protein</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Carboplatin</subject><subject>Carboplatin - therapeutic use</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell division</subject><subject>Chemotherapy</subject><subject>Cystadenocarcinoma, Serous - drug therapy</subject><subject>DNA damage</subject><subject>Female</subject><subject>Gene expression</subject><subject>Humans</subject><subject>K-Ras protein</subject><subject>Kinases</subject><subject>Malignancy</subject><subject>Medical prognosis</subject><subject>Mutation</subject><subject>Neoplasm Recurrence, Local - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gasimli, Khayal</au><au>Raab, Monika</au><au>Tahmasbi Rad, Morva</au><au>Kurunci-Csacsko, Elisabeth</au><au>Becker, Sven</au><au>Strebhardt, Klaus</au><au>Sanhaji, Mourad</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2022-09-17</date><risdate>2022</risdate><volume>23</volume><issue>18</issue><spage>10892</spage><pages>10892-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36142803</pmid><doi>10.3390/ijms231810892</doi><orcidid>https://orcid.org/0000-0001-8202-0694</orcidid><orcidid>https://orcid.org/0000-0003-1874-0341</orcidid><orcidid>https://orcid.org/0000-0003-2173-9763</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2022-09, Vol.23 (18), p.10892 |
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| language | eng |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Apoptosis BRCA1 protein BRCA1 Protein - genetics BRCA2 protein Breast cancer Cancer therapies Carboplatin Carboplatin - therapeutic use Cell cycle Cell Cycle Proteins - metabolism Cell division Chemotherapy Cystadenocarcinoma, Serous - drug therapy DNA damage Female Gene expression Humans K-Ras protein Kinases Malignancy Medical prognosis Mutation Neoplasm Recurrence, Local - drug therapy Neoplasm Recurrence, Local - genetics Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Patients Phthalazines - pharmacology Point mutation Polo-Like Kinase 1 Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Protein Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins p21(ras) - genetics Spheroids Targeted cancer therapy Tumors |
| title | Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification |
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