The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER + breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully charac...
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creator | Soria-Bretones, Isabel Thu, Kelsie L. Silvester, Jennifer Cruickshank, Jennifer El Ghamrasni, Samah Ba-alawi, Wail Fletcher, Graham C. Kiarash, Reza Elliott, Mitchell J. Chalmers, Jordan J. Elia, Andrea C. Cheng, Albert Rose, April A. N. Bray, Mark R. Haibe-Kains, Benjamin Mak, Tak W. Cescon, David W. |
description | Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER
+
breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B.
RB1
loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER
+
breast cancer patients who develop resistance to CDK4/6i.
The TTK inhibitor CFI-402257 is a potential therapy for some cyclin-dependent kinase 4/6 inhibitor-resistant ER
+
breast cancers. |
doi_str_mv | 10.1126/sciadv.abq4293 |
format | Article |
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+
breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B.
RB1
loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER
+
breast cancer patients who develop resistance to CDK4/6i.
The TTK inhibitor CFI-402257 is a potential therapy for some cyclin-dependent kinase 4/6 inhibitor-resistant ER
+
breast cancers.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.abq4293</identifier><identifier>PMID: 36070391</identifier><language>eng</language><publisher>American Association for the Advancement of Science</publisher><subject>Biomedicine and Life Sciences ; Cancer ; SciAdv r-articles</subject><ispartof>Science advances, 2022-09, Vol.8 (36), p.eabq4293-eabq4293</ispartof><rights>Copyright © 2022 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). 2022 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c367t-43e4bd957ed30ca12870c4d00abd5d8b5947e7d98b9c9a2111cd4805072ba8013</citedby><cites>FETCH-LOGICAL-c367t-43e4bd957ed30ca12870c4d00abd5d8b5947e7d98b9c9a2111cd4805072ba8013</cites><orcidid>0000-0001-7079-4772 ; 0000-0003-3620-0373 ; 0000-0001-6711-7287 ; 0000-0001-9309-754X ; 0000-0002-8656-3386 ; 0000-0003-4609-6127 ; 0000-0002-9845-4603 ; 0000-0002-1080-0998 ; 0000-0001-6766-861X ; 0000-0002-2747-4703 ; 0000-0001-9262-7238 ; 0000-0002-5548-7077</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/PMC9451148/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451148/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Soria-Bretones, Isabel</creatorcontrib><creatorcontrib>Thu, Kelsie L.</creatorcontrib><creatorcontrib>Silvester, Jennifer</creatorcontrib><creatorcontrib>Cruickshank, Jennifer</creatorcontrib><creatorcontrib>El Ghamrasni, Samah</creatorcontrib><creatorcontrib>Ba-alawi, Wail</creatorcontrib><creatorcontrib>Fletcher, Graham C.</creatorcontrib><creatorcontrib>Kiarash, Reza</creatorcontrib><creatorcontrib>Elliott, Mitchell J.</creatorcontrib><creatorcontrib>Chalmers, Jordan J.</creatorcontrib><creatorcontrib>Elia, Andrea C.</creatorcontrib><creatorcontrib>Cheng, Albert</creatorcontrib><creatorcontrib>Rose, April A. N.</creatorcontrib><creatorcontrib>Bray, Mark R.</creatorcontrib><creatorcontrib>Haibe-Kains, Benjamin</creatorcontrib><creatorcontrib>Mak, Tak W.</creatorcontrib><creatorcontrib>Cescon, David W.</creatorcontrib><title>The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations</title><title>Science advances</title><description>Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER
+
breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B.
RB1
loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER
+
breast cancer patients who develop resistance to CDK4/6i.
The TTK inhibitor CFI-402257 is a potential therapy for some cyclin-dependent kinase 4/6 inhibitor-resistant ER
+
breast cancers.</description><subject>Biomedicine and Life Sciences</subject><subject>Cancer</subject><subject>SciAdv r-articles</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNpVkU1v1DAQhiNERau2V84-IqHd2rETxxcktJQPUQmpKmdrbM8SQ2KntrPV3jhz5R_yS5pqVwhOM6N55pnDW1UvGV0zVrdX2XpwuzWYe1Er_qw6q7lsVnUjuuf_9KfVZc7fKaVMtG3D1IvqlLdUUq7YWfXrrkeSJx_cgARyxtEMe2J7tD-m6EMhPhMgpccEE87FW7Kbh7BMxg--7Encks27z-KqJT703vgS05-fvxNmnwss59e35DUxCSEXYiFYTOTBl56MC_lkA4MpQfEx5IvqZAtDxstjPa--vr--23xc3Xz58Gnz9mZleSvLSnAUxqlGouPUAqs7Sa1wlIJxjetMo4RE6VRnlFVQM8asEx1tqKwNdJTx8-rNwTvNZkRnMZQEg56SHyHtdQSv_98E3-tvcaeVaBgT3SJ4dRSkeD9jLnr02eIwQMA4Z11LxjrBhRALuj6gNsWcE27_vmFUP2WoDxnqY4b8ESuBlBI</recordid><startdate>20220909</startdate><enddate>20220909</enddate><creator>Soria-Bretones, Isabel</creator><creator>Thu, Kelsie L.</creator><creator>Silvester, Jennifer</creator><creator>Cruickshank, Jennifer</creator><creator>El Ghamrasni, Samah</creator><creator>Ba-alawi, Wail</creator><creator>Fletcher, Graham C.</creator><creator>Kiarash, Reza</creator><creator>Elliott, Mitchell J.</creator><creator>Chalmers, Jordan J.</creator><creator>Elia, Andrea C.</creator><creator>Cheng, Albert</creator><creator>Rose, April A. 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N. ; Bray, Mark R. ; Haibe-Kains, Benjamin ; Mak, Tak W. ; Cescon, David W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c367t-43e4bd957ed30ca12870c4d00abd5d8b5947e7d98b9c9a2111cd4805072ba8013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Biomedicine and Life Sciences</topic><topic>Cancer</topic><topic>SciAdv r-articles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Soria-Bretones, Isabel</creatorcontrib><creatorcontrib>Thu, Kelsie L.</creatorcontrib><creatorcontrib>Silvester, Jennifer</creatorcontrib><creatorcontrib>Cruickshank, Jennifer</creatorcontrib><creatorcontrib>El Ghamrasni, Samah</creatorcontrib><creatorcontrib>Ba-alawi, Wail</creatorcontrib><creatorcontrib>Fletcher, Graham C.</creatorcontrib><creatorcontrib>Kiarash, Reza</creatorcontrib><creatorcontrib>Elliott, Mitchell J.</creatorcontrib><creatorcontrib>Chalmers, Jordan J.</creatorcontrib><creatorcontrib>Elia, Andrea C.</creatorcontrib><creatorcontrib>Cheng, Albert</creatorcontrib><creatorcontrib>Rose, April A. N.</creatorcontrib><creatorcontrib>Bray, Mark R.</creatorcontrib><creatorcontrib>Haibe-Kains, Benjamin</creatorcontrib><creatorcontrib>Mak, Tak W.</creatorcontrib><creatorcontrib>Cescon, David W.</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</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>Soria-Bretones, Isabel</au><au>Thu, Kelsie L.</au><au>Silvester, Jennifer</au><au>Cruickshank, Jennifer</au><au>El Ghamrasni, Samah</au><au>Ba-alawi, Wail</au><au>Fletcher, Graham C.</au><au>Kiarash, Reza</au><au>Elliott, Mitchell J.</au><au>Chalmers, Jordan J.</au><au>Elia, Andrea C.</au><au>Cheng, Albert</au><au>Rose, April A. N.</au><au>Bray, Mark R.</au><au>Haibe-Kains, Benjamin</au><au>Mak, Tak W.</au><au>Cescon, David W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations</atitle><jtitle>Science advances</jtitle><date>2022-09-09</date><risdate>2022</risdate><volume>8</volume><issue>36</issue><spage>eabq4293</spage><epage>eabq4293</epage><pages>eabq4293-eabq4293</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER
+
breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B.
RB1
loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER
+
breast cancer patients who develop resistance to CDK4/6i.
The TTK inhibitor CFI-402257 is a potential therapy for some cyclin-dependent kinase 4/6 inhibitor-resistant ER
+
breast cancers.</abstract><pub>American Association for the Advancement of Science</pub><pmid>36070391</pmid><doi>10.1126/sciadv.abq4293</doi><orcidid>https://orcid.org/0000-0001-7079-4772</orcidid><orcidid>https://orcid.org/0000-0003-3620-0373</orcidid><orcidid>https://orcid.org/0000-0001-6711-7287</orcidid><orcidid>https://orcid.org/0000-0001-9309-754X</orcidid><orcidid>https://orcid.org/0000-0002-8656-3386</orcidid><orcidid>https://orcid.org/0000-0003-4609-6127</orcidid><orcidid>https://orcid.org/0000-0002-9845-4603</orcidid><orcidid>https://orcid.org/0000-0002-1080-0998</orcidid><orcidid>https://orcid.org/0000-0001-6766-861X</orcidid><orcidid>https://orcid.org/0000-0002-2747-4703</orcidid><orcidid>https://orcid.org/0000-0001-9262-7238</orcidid><orcidid>https://orcid.org/0000-0002-5548-7077</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Biomedicine and Life Sciences Cancer SciAdv r-articles |
title | The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations |
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