A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells
Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB...
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| creator | Bulanova, Daria Akimov, Yevhen Senkowski, Wojciech Oikkonen, Jaana Gall-Mas, Laura Timonen, Sanna Elmadani, Manar Hynninen, Johanna Hautaniemi, Sampsa Aittokallio, Tero Wennerberg, Krister |
| description | Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death. CK2 inhibition was also effective in primary patient-derived cells. It selectively prevented the regrowth of RB1-deficient patient HGSC organoids after treatment with carboplatin or niraparib. As about 25% of HGSCs and 40% of TNBCs have lost RB1 expression, CK2 inhibition is a promising approach to overcome resistance to standard therapeutics in large strata of patients. |
| doi_str_mv | 10.1126/sciadv.adj1564 |
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Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death. CK2 inhibition was also effective in primary patient-derived cells. It selectively prevented the regrowth of RB1-deficient patient HGSC organoids after treatment with carboplatin or niraparib. As about 25% of HGSCs and 40% of TNBCs have lost RB1 expression, CK2 inhibition is a promising approach to overcome resistance to standard therapeutics in large strata of patients.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.adj1564</identifier><identifier>PMID: 38781347</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Antineoplastic Agents - pharmacology ; Biomedicine and Life Sciences ; Cancer ; Carboplatin - pharmacology ; Casein Kinase II - antagonists & inhibitors ; Casein Kinase II - genetics ; Casein Kinase II - metabolism ; Cell Biology ; Cell Line, Tumor ; DNA Replication - drug effects ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Female ; Humans ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Retinoblastoma Binding Proteins - genetics ; Retinoblastoma Binding Proteins - metabolism ; SciAdv r-articles ; Synthetic Lethal Mutations ; Triple Negative Breast Neoplasms - drug therapy ; Triple Negative Breast Neoplasms - genetics ; Triple Negative Breast Neoplasms - metabolism ; Triple Negative Breast Neoplasms - pathology ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>Science advances, 2024-05, Vol.10 (21), p.eadj1564-eadj1564</ispartof><rights>info:eu-repo/semantics/openAccess</rights><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2024 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c371t-fb0a2e792e353590aa90253933659d94f762239d89294a9360adc89ce81211573</cites><orcidid>0000-0002-1063-2736 ; 0000-0002-7749-2694 ; 0000-0002-5038-1724 ; 0000-0002-8139-5950 ; 0000-0003-0413-2564 ; 0000-0002-0854-7225 ; 0000-0001-8120-1944 ; 0000-0002-0420-2334 ; 0000-0002-0886-9769 ; 0000-0002-1352-4220</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/PMC11114247/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11114247/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,26567,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38781347$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bulanova, Daria</creatorcontrib><creatorcontrib>Akimov, Yevhen</creatorcontrib><creatorcontrib>Senkowski, Wojciech</creatorcontrib><creatorcontrib>Oikkonen, Jaana</creatorcontrib><creatorcontrib>Gall-Mas, Laura</creatorcontrib><creatorcontrib>Timonen, Sanna</creatorcontrib><creatorcontrib>Elmadani, Manar</creatorcontrib><creatorcontrib>Hynninen, Johanna</creatorcontrib><creatorcontrib>Hautaniemi, Sampsa</creatorcontrib><creatorcontrib>Aittokallio, Tero</creatorcontrib><creatorcontrib>Wennerberg, Krister</creatorcontrib><title>A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death. CK2 inhibition was also effective in primary patient-derived cells. It selectively prevented the regrowth of RB1-deficient patient HGSC organoids after treatment with carboplatin or niraparib. As about 25% of HGSCs and 40% of TNBCs have lost RB1 expression, CK2 inhibition is a promising approach to overcome resistance to standard therapeutics in large strata of patients.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Biomedicine and Life Sciences</subject><subject>Cancer</subject><subject>Carboplatin - pharmacology</subject><subject>Casein Kinase II - antagonists & inhibitors</subject><subject>Casein Kinase II - genetics</subject><subject>Casein Kinase II - metabolism</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>DNA Replication - drug effects</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</subject><subject>Retinoblastoma Binding Proteins - genetics</subject><subject>Retinoblastoma Binding Proteins - metabolism</subject><subject>SciAdv r-articles</subject><subject>Synthetic Lethal Mutations</subject><subject>Triple Negative Breast Neoplasms - drug therapy</subject><subject>Triple Negative Breast Neoplasms - genetics</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>3HK</sourceid><recordid>eNpVkc1rGzEQxUVpaYKba49Fx17W0efu6hTSkC8IFEp7FrI0GytZS1tJa_Cx_3ll7IREFz2hN7-Z4SH0lZIlpaw9z9Ybt10a90RlKz6gU8Y72TAp-o9v9Ak6y_mJEEJF20qqPqMT3nc95aI7Rf8ucd6FsobiLR6hrM2IHUwQHAS7wzFgazL4gJ99qAIzXHWCPMVQXyVWPY3emuJjaCZIZU4rHx5xJSYzwVyxeV_y6wdtHAzeegilMoOFhC2MY_6CPg1mzHB2vBfoz83176u75uHn7f3V5UNjeUdLM6yIYdApBlxyqYgxijDJFeetVE6JoWsZ48r1iilhFG-JcbZXFnrKKJUdX6CLA3eaVxtwts6RzKin5Dcm7XQ0Xr__CX6tH-NW03oEE3sCPhBs8rn4oENMRlPSS1ZNQtX-C_T92CTFvzPkojc-79c0AeKcNSctqbn0Ha3W5Qst5pxgeB2FEr2PVx_i1cd4a8G3twu82l_C5P8BSoWiwA</recordid><startdate>20240524</startdate><enddate>20240524</enddate><creator>Bulanova, Daria</creator><creator>Akimov, Yevhen</creator><creator>Senkowski, Wojciech</creator><creator>Oikkonen, Jaana</creator><creator>Gall-Mas, Laura</creator><creator>Timonen, Sanna</creator><creator>Elmadani, Manar</creator><creator>Hynninen, Johanna</creator><creator>Hautaniemi, Sampsa</creator><creator>Aittokallio, Tero</creator><creator>Wennerberg, Krister</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>3HK</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1063-2736</orcidid><orcidid>https://orcid.org/0000-0002-7749-2694</orcidid><orcidid>https://orcid.org/0000-0002-5038-1724</orcidid><orcidid>https://orcid.org/0000-0002-8139-5950</orcidid><orcidid>https://orcid.org/0000-0003-0413-2564</orcidid><orcidid>https://orcid.org/0000-0002-0854-7225</orcidid><orcidid>https://orcid.org/0000-0001-8120-1944</orcidid><orcidid>https://orcid.org/0000-0002-0420-2334</orcidid><orcidid>https://orcid.org/0000-0002-0886-9769</orcidid><orcidid>https://orcid.org/0000-0002-1352-4220</orcidid></search><sort><creationdate>20240524</creationdate><title>A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells</title><author>Bulanova, Daria ; Akimov, Yevhen ; Senkowski, Wojciech ; Oikkonen, Jaana ; Gall-Mas, Laura ; Timonen, Sanna ; Elmadani, Manar ; Hynninen, Johanna ; Hautaniemi, Sampsa ; Aittokallio, Tero ; Wennerberg, Krister</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c371t-fb0a2e792e353590aa90253933659d94f762239d89294a9360adc89ce81211573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Biomedicine and Life Sciences</topic><topic>Cancer</topic><topic>Carboplatin - pharmacology</topic><topic>Casein Kinase II - antagonists & inhibitors</topic><topic>Casein Kinase II - genetics</topic><topic>Casein Kinase II - metabolism</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>DNA Replication - drug effects</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Female</topic><topic>Humans</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</topic><topic>Retinoblastoma Binding Proteins - genetics</topic><topic>Retinoblastoma Binding Proteins - metabolism</topic><topic>SciAdv r-articles</topic><topic>Synthetic Lethal Mutations</topic><topic>Triple Negative Breast Neoplasms - drug therapy</topic><topic>Triple Negative Breast Neoplasms - genetics</topic><topic>Triple Negative Breast Neoplasms - metabolism</topic><topic>Triple Negative Breast Neoplasms - pathology</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bulanova, Daria</creatorcontrib><creatorcontrib>Akimov, Yevhen</creatorcontrib><creatorcontrib>Senkowski, Wojciech</creatorcontrib><creatorcontrib>Oikkonen, Jaana</creatorcontrib><creatorcontrib>Gall-Mas, Laura</creatorcontrib><creatorcontrib>Timonen, Sanna</creatorcontrib><creatorcontrib>Elmadani, Manar</creatorcontrib><creatorcontrib>Hynninen, Johanna</creatorcontrib><creatorcontrib>Hautaniemi, Sampsa</creatorcontrib><creatorcontrib>Aittokallio, Tero</creatorcontrib><creatorcontrib>Wennerberg, Krister</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>NORA - Norwegian Open Research Archives</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bulanova, Daria</au><au>Akimov, Yevhen</au><au>Senkowski, Wojciech</au><au>Oikkonen, Jaana</au><au>Gall-Mas, Laura</au><au>Timonen, Sanna</au><au>Elmadani, Manar</au><au>Hynninen, Johanna</au><au>Hautaniemi, Sampsa</au><au>Aittokallio, Tero</au><au>Wennerberg, Krister</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2024-05-24</date><risdate>2024</risdate><volume>10</volume><issue>21</issue><spage>eadj1564</spage><epage>eadj1564</epage><pages>eadj1564-eadj1564</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death. CK2 inhibition was also effective in primary patient-derived cells. It selectively prevented the regrowth of RB1-deficient patient HGSC organoids after treatment with carboplatin or niraparib. 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| subjects | Antineoplastic Agents - pharmacology Biomedicine and Life Sciences Cancer Carboplatin - pharmacology Casein Kinase II - antagonists & inhibitors Casein Kinase II - genetics Casein Kinase II - metabolism Cell Biology Cell Line, Tumor DNA Replication - drug effects Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Female Humans Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Retinoblastoma Binding Proteins - genetics Retinoblastoma Binding Proteins - metabolism SciAdv r-articles Synthetic Lethal Mutations Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - pathology Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism |
| title | A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells |
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