PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that...
Gespeichert in:
| Veröffentlicht in: | British journal of cancer Jg. 129; H. 8; S. 1238 - 1250 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
England
Nature Publishing Group
12.10.2023
|
| Schlagworte: | |
| ISSN: | 0007-0920, 1532-1827, 1532-1827 |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Abstract | Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases.
We utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib.
Palbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation.
Resistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach. |
|---|---|
| AbstractList | BackgroundCyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases.MethodsWe utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib.ResultsPalbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation.ConclusionResistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases. We utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib. Palbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation. Resistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases.BACKGROUNDCyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases.We utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib.METHODSWe utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib.Palbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation.RESULTSPalbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation.Resistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach.CONCLUSIONResistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach. |
| Author | Zhao, Bosheng Rubin, Seth M Kumarasamy, Vishnu Knudsen, Erik S Gao, Zhe Burgess, Kevin Jiang, Baishan Witkiewicz, Agnieszka K |
| Author_xml | – sequence: 1 givenname: Vishnu surname: Kumarasamy fullname: Kumarasamy, Vishnu organization: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA – sequence: 2 givenname: Zhe surname: Gao fullname: Gao, Zhe organization: Department of Chemistry, Texas A&M University, Box 30012, College Station, TX, USA – sequence: 3 givenname: Bosheng surname: Zhao fullname: Zhao, Bosheng organization: Department of Chemistry, Texas A&M University, Box 30012, College Station, TX, USA – sequence: 4 givenname: Baishan orcidid: 0000-0001-6796-9500 surname: Jiang fullname: Jiang, Baishan organization: Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China – sequence: 5 givenname: Seth M surname: Rubin fullname: Rubin, Seth M organization: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA – sequence: 6 givenname: Kevin surname: Burgess fullname: Burgess, Kevin organization: Department of Chemistry, Texas A&M University, Box 30012, College Station, TX, USA – sequence: 7 givenname: Agnieszka K surname: Witkiewicz fullname: Witkiewicz, Agnieszka K organization: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA – sequence: 8 givenname: Erik S orcidid: 0000-0002-5130-5969 surname: Knudsen fullname: Knudsen, Erik S email: Erik.Knudsen@roswellpark.org organization: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA. Erik.Knudsen@roswellpark.org |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/37626264$$D View this record in MEDLINE/PubMed |
| BookMark | eNpdkE1LAzEQhoNU7If-AQ8S8OJlNdlkN9ljWT-xUJF6LmkyqanbbN1kD_33plgvMgzDwMPLyzNGA996QOiSkltKmLwLnHJaZiRnh62qjJ-gES1YnlGZiwEaEUJERqqcDNE4hE16KyLFGRoyUeZp-Aj1b-_zxbTOtmCcimBwff-KDaw7ZVR0rcfGWQsd-OhU0-yx2-6UjgFr5TV0WEPTYL3XDQRsesCxxZ8QoWvX4MHFxHv85bwKkEJ34A147SCco1OrmgAXxztBH48Pi_o5m82fXurpLNNcFDGjjFBREk2YMCsurKVVQaxdEaOo0sSKQtuSS22YNiVQkMxKQ0FABQXI5GiCbn5zd1373UOIy60Lh87KQ9uHZS4LIbkQtEzo9T900_adT-0SJUpRcsJZoq6OVL9Kypa7zm1Vt1_-CWU_UMt6rg |
| CitedBy_id | crossref_primary_10_3390_biom15020206 crossref_primary_10_1631_jzus_B2500021 crossref_primary_10_1016_j_seminoncol_2025_152395 crossref_primary_10_1016_j_jconrel_2024_11_076 crossref_primary_10_1096_fj_202401788RR crossref_primary_10_1002_cmdc_202400267 crossref_primary_10_1016_j_molstruc_2024_141273 crossref_primary_10_3390_ijms25105067 crossref_primary_10_1002_mco2_70258 crossref_primary_10_1016_j_ejcped_2024_100182 |
| ContentType | Journal Article |
| Copyright | 2023. The Author(s), under exclusive licence to Springer Nature Limited. The Author(s), under exclusive licence to Springer Nature Limited 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
| Copyright_xml | – notice: 2023. The Author(s), under exclusive licence to Springer Nature Limited. – notice: The Author(s), under exclusive licence to Springer Nature Limited 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
| DBID | CGR CUY CVF ECM EIF NPM 3V. 7RV 7TO 7U9 7X7 7XB 88E 8AO 8C1 8FE 8FH 8FI 8FJ 8FK ABUWG AFKRA AN0 AZQEC BBNVY BENPR BHPHI CCPQU DWQXO FYUFA GHDGH GNUQQ H94 HCIFZ K9. KB0 LK8 M0S M1P M7P NAPCQ PHGZM PHGZT PJZUB PKEHL PPXIY PQEST PQGLB PQQKQ PQUKI PRINS 7X8 |
| DOI | 10.1038/s41416-023-02399-4 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed ProQuest Central (Corporate) Nursing & Allied Health Database Oncogenes and Growth Factors Abstracts Virology and AIDS Abstracts Health & Medical Collection ProQuest Central (purchase pre-March 2016) Medical Database (Alumni Edition) ProQuest Pharma Collection Public Health Database ProQuest SciTech Collection ProQuest Natural Science Journals Hospital Premium Collection Hospital Premium Collection (Alumni Edition) ProQuest Central (Alumni) (purchase pre-March 2016) ProQuest Central (Alumni) ProQuest Central UK/Ireland British Nursing Database (Proquest) ProQuest Central Essentials Biological Science Database (Proquest) ProQuest Central Natural Science Collection ProQuest One Community College ProQuest Central Health Research Premium Collection Health Research Premium Collection (Alumni) ProQuest Central Student AIDS and Cancer Research Abstracts SciTech Premium Collection ProQuest Health & Medical Complete (Alumni) Nursing & Allied Health Database (Alumni Edition) Biological Sciences ProQuest Health & Medical Collection PML(ProQuest Medical Library) Biological Science Database Nursing & Allied Health Premium ProQuest Central Premium ProQuest One Academic ProQuest Health & Medical Research Collection ProQuest One Academic Middle East (New) One Health & Nursing ProQuest One Academic Eastern Edition (DO NOT USE) One Applied & Life Sciences ProQuest One Academic (retired) ProQuest One Academic UKI Edition ProQuest Central China MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) ProQuest Central Student Oncogenes and Growth Factors Abstracts ProQuest One Academic Middle East (New) ProQuest Central Essentials ProQuest Health & Medical Complete (Alumni) ProQuest Central (Alumni Edition) SciTech Premium Collection ProQuest One Community College ProQuest One Health & Nursing ProQuest Natural Science Collection ProQuest Pharma Collection ProQuest Central China ProQuest Central ProQuest One Applied & Life Sciences ProQuest Health & Medical Research Collection Health Research Premium Collection Health and Medicine Complete (Alumni Edition) Natural Science Collection ProQuest Central Korea Health & Medical Research Collection Biological Science Collection AIDS and Cancer Research Abstracts ProQuest Central (New) ProQuest Medical Library (Alumni) ProQuest Public Health Virology and AIDS Abstracts ProQuest Biological Science Collection ProQuest One Academic Eastern Edition British Nursing Index with Full Text ProQuest Nursing & Allied Health Source ProQuest Hospital Collection Health Research Premium Collection (Alumni) Biological Science Database ProQuest SciTech Collection ProQuest Hospital Collection (Alumni) Nursing & Allied Health Premium ProQuest Health & Medical Complete ProQuest Medical Library ProQuest One Academic UKI Edition ProQuest Nursing & Allied Health Source (Alumni) ProQuest One Academic ProQuest One Academic (New) ProQuest Central (Alumni) MEDLINE - Academic |
| DatabaseTitleList | ProQuest Central Student MEDLINE MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7RV name: Nursing & Allied Health Database url: https://search.proquest.com/nahs sourceTypes: Aggregation Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Medicine |
| EISSN | 1532-1827 |
| EndPage | 1250 |
| ExternalDocumentID | 37626264 |
| Genre | Journal Article |
| GrantInformation_xml | – fundername: NIGMS NIH HHS grantid: R35 GM145255 – fundername: NCI NIH HHS grantid: R01 CA267647 – fundername: NCI NIH HHS grantid: R01 CA247362 |
| GroupedDBID | --- -Q- .55 .GJ 0R~ 23N 36B 39C 4.4 406 53G 5GY 5RE 6J9 70F 7RV 7X7 88E 8AO 8C1 8FI 8FJ 8R4 8R5 8WZ A6W AACDK AANZL AASML AATNV AAWTL AAYZH ABAKF ABAWZ ABDBE ABDBF ABLJU ABOCM ABUWG ABZZP ACAOD ACGFO ACGFS ACKTT ACPRK ACRQY ACUHS ACZOJ ADBBV ADFRT AEFQL AEJRE AEMSY AENEX AEVLU AEXYK AFBBN AFKRA AFRAH AFSHS AGAYW AGHAI AGQEE AHMBA AHSBF AI. AIGIU AILAN AJRNO ALFFA ALMA_UNASSIGNED_HOLDINGS AMYLF AN0 AOIJS ASPBG AVWKF AXYYD AYFIA AZFZN B0M BAWUL BBNVY BENPR BHPHI BKEYQ BKKNO BNQBC BPHCQ BVXVI CAG CCPQU CGR COF CS3 CUY CVF DIK DNIVK DPUIP DU5 E3Z EAD EAP EAS EBC EBD EBLON EBS ECM EE. EIF EIOEI EJD EMB EMK EMOBN EPL ESX EX3 F5P FDQFY FEDTE FERAY FIGPU FIZPM FRJ FSGXE FYUFA GX1 HCIFZ HMCUK HVGLF HYE HZ~ IH2 IWAJR J5H JSO JZLTJ KQ8 M1P M41 M7P NAPCQ NPM NQJWS O9- OK1 P2P PHGZT PQQKQ PROAC PSQYO Q2X RNT RNTTT ROL RPM SNX SNYQT SOHCF SOJ SRMVM SV3 SWTZT TAOOD TBHMF TDRGL TR2 TUS UDS UKHRP VH1 W2D WH7 WOW X7M Y6R ZGI ~02 ~8M 3V. 7TO 7U9 7XB 8FE 8FH 8FK AAFWJ ABBRH ABFSG ABRTQ ACSTC AEZWR AFDZB AFHIU AHWEU AIXLP ATHPR AZQEC DWQXO GNUQQ H94 K9. LK8 PHGZM PJZUB PKEHL PPXIY PQEST PQGLB PQUKI PRINS 7X8 PUEGO |
| ID | FETCH-LOGICAL-c475t-1301760c037db47ff1950ffb0da1ac0f75cf648cd3cd6e1e83f8d1e7e9e5e8103 |
| IEDL.DBID | M7P |
| ISICitedReferencesCount | 12 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=001059897700001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 0007-0920 1532-1827 |
| IngestDate | Sun Sep 28 10:23:10 EDT 2025 Tue Oct 07 05:11:43 EDT 2025 Thu Apr 03 07:00:52 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 8 |
| Language | English |
| License | 2023. The Author(s), under exclusive licence to Springer Nature Limited. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c475t-1301760c037db47ff1950ffb0da1ac0f75cf648cd3cd6e1e83f8d1e7e9e5e8103 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
| ORCID | 0000-0002-5130-5969 0000-0001-6796-9500 |
| OpenAccessLink | https://pmc.ncbi.nlm.nih.gov/articles/PMC10575895/pdf/41416_2023_Article_2399.pdf |
| PMID | 37626264 |
| PQID | 2876764043 |
| PQPubID | 41855 |
| PageCount | 13 |
| ParticipantIDs | proquest_miscellaneous_2857847716 proquest_journals_2876764043 pubmed_primary_37626264 |
| PublicationCentury | 2000 |
| PublicationDate | 2023-10-12 |
| PublicationDateYYYYMMDD | 2023-10-12 |
| PublicationDate_xml | – month: 10 year: 2023 text: 2023-10-12 day: 12 |
| PublicationDecade | 2020 |
| PublicationPlace | England |
| PublicationPlace_xml | – name: England – name: London |
| PublicationTitle | British journal of cancer |
| PublicationTitleAlternate | Br J Cancer |
| PublicationYear | 2023 |
| Publisher | Nature Publishing Group |
| Publisher_xml | – name: Nature Publishing Group |
| SSID | ssj0009087 |
| Score | 2.495856 |
| Snippet | Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We... BackgroundCyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle.... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 1238 |
| SubjectTerms | Animals Cell activation Cell cycle Cell Cycle - drug effects Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Chimeras Cyclin E Cyclin-dependent kinase 2 Cyclin-dependent kinase 4 Cyclin-Dependent Kinase 4 - antagonists & inhibitors Cyclin-Dependent Kinase 4 - metabolism Cyclin-Dependent Kinase 6 - antagonists & inhibitors Cyclin-Dependent Kinase 6 - metabolism Cyclin-dependent kinases Humans INK4a protein Kinases Mice Organoids p16 Protein Piperazines - pharmacology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Proteolysis Proteolysis - drug effects Pyridines - chemistry Pyridines - pharmacology Thalidomide - analogs & derivatives Thalidomide - pharmacology Tumors Xenograft Model Antitumor Assays |
| Title | PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/37626264 https://www.proquest.com/docview/2876764043 https://www.proquest.com/docview/2857847716 |
| Volume | 129 |
| WOSCitedRecordID | wos001059897700001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1Na9wwEB2apJRc0u9023RRoVcR2ZYl-VTSbUKhzdYsadjbYuuDLgl2st4t5N9nRvY2p_ZSDHOxMbY8Gj2NZ94D-IiYoSYicZ4UWnBpZeBFHQxXhapIPs5VMXVx-V1Pp2Y-L8oh4dYNZZXbmBgDtWst5ciPEdkrrYgL5tPNLSfVKPq7Okho7MAesSRksXSvfCDdFabnzKR0XJGKoWlGZOa4kwlCEY4rFo_tnVz-HWLGpebs6f8-5DM4GEAmO-m94jk88s0LeHI-_EZ_CZty9uPiZMJj2whCTjb58o05oo3oFZbYVjYFp__19R3rWyk7ZslFVoyS_czeUT0dcxvP1i37RVU1LTqjR1TPlg27Wja4PrKtxi5GkO4V_Dw7vZh85YP-ArdS56RSj9NVCSsy7WqpQyDJ2BBq4aqksiLo3AYljXWZdcon3mTBuMRrX_jcGxzm17DbtI1_A8yGVAVdF76uccMT8sriPsWI1FdVqlXIR3C0HdDFMIm6xcNojuDDn9Po_vSaVePbDV2DIUdq3PWN4LD_aIubnqdjgbEzxUO-_ffN38E-acjzWKZyBLvr1ca_h8f293rZrcawo2eXZOc6WoPWTJIx7H0-nZazcfQ4tNPy_B48s9q- |
| linkProvider | ProQuest |
| linkToHtml | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMw1V1Lb9QwEB6VgoAL5VmWFjASHK06iRM7B1RVW6pWu12qaql6SxM_xKpVUja7oP1T_EZm8mhPcOsB5ZjIkuPP38zYM_MBfESfoaBG4jxIleDSSM_TwmuepElO8nE2b44uzsZqMtHn5-nJGvzua2EorbLnxIaobWXojHwHPftEJdQLZvf6ByfVKLpd7SU0WliM3OoXhmz156N9XN9PYXjwZTo85J2qADdSxaS9jiBMhBGRsoVU3pMQqveFsHmQG-FVbHwitbGRsYkLnI68toFTLnWx04GIcNx7cB95PKAUMnV6dtvkV-i2Rycd_6Wh6Ip0RKR3ahmg68PRQvKmnJTLv7u0jWk72PjffspTeNI50WyvRf0zWHPlc3h43KUJvIDlyenX6d6QN2Ux6FKz4f6IWWqL0SpIsV4WBunt6mrF2lLRmhnaAnNGlxnMrChfkNmlY4uKfaesoQo3m8Oohc1Kdjkr0f6zXkMYGbJ-Cd_uZNKvYL2sSvcamPFh4lWRuqLAgM7HucE4TIvQ5XmoEh8PYLtfwKwjiTq7Xb0BfLh5jdubppmXrlrSN0ipUmFUO4DNFiTZdduHJEPbEOIj3_x78Pfw6HB6PM7GR5PRFjwOCYNNSs42rC_mS_cWHpifi1k9f9egmcHFXSPlDzmwMvk |
| linkToPdf | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMw1V1Lb9NAEB6Vgiou5VkaKLBIcFxl_dpdH1BVJURUKSFCBfVm7H2IiMpu46Qof41f1xk_6AluPSAfba203m9mZ3a_mQ_gLcYMBTUS50GqBI9N7HlaeM1lKnOSj7N5c3Tx7UTNZvrsLJ1vwe--FoZolb1PbBy1rQydkQ8xspdKUi-Yoe9oEfPx5PDikpOCFN209nIaLUSmbvML07f6_fEY1_pdGE4-nI4-8k5hgJtYJaTDjoCUwohI2SJW3pMoqveFsHmQG-FVYryMtbGRsdIFTkde28Apl7rE6UBEOO4duKsiRDFVqY9u6CWp0G2_TjoKTEPRFeyISA_rOMAwiONuyZvSUh7_PbxttrnJg__5Bz2E3S64ZketNTyCLVc-hp1PHX3gCaznXz6fHo14Uy6DoTYbjafMUruMVlmK9XIx6PbOzzesLSGtmSHTWDK65GBmQzxCZteOrSr2g9hEFRqhw2yGLUr2c1FiXMB6bWH0nPVT-Hork96D7bIq3T4w40PpVZG6osBEzye5wfxMi9DleaikTwZw0C9m1jmPOrtZyQG8-fMazZ6mmZeuWtM36GpjhdnuAJ61gMku2v4kGe4ZIT7x838P_hp2ECDZyfFs-gLuhwTHhqlzANur5dq9hHvmarWol68aYDP4fttAuQYGZjtU |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=PROTAC-mediated+CDK+degradation+differentially+impacts+cancer+cell+cycles+due+to+heterogeneity+in+kinase+dependencies&rft.jtitle=British+journal+of+cancer&rft.au=Kumarasamy%2C+Vishnu&rft.au=Gao%2C+Zhe&rft.au=Zhao%2C+Bosheng&rft.au=Jiang%2C+Baishan&rft.date=2023-10-12&rft.pub=Nature+Publishing+Group&rft.issn=0007-0920&rft.eissn=1532-1827&rft.volume=129&rft.issue=8&rft.spage=1238&rft.epage=1250&rft_id=info:doi/10.1038%2Fs41416-023-02399-4&rft.externalDBID=HAS_PDF_LINK |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0007-0920&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0007-0920&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0007-0920&client=summon |