Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity
Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of...
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| Ձևաչափ: | Internet publication |
| Լեզու: | English |
| Հրապարակվել է: |
2024
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| _version_ | 1826317622163013632 |
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| author | Singh, S Gleason, CE Fang, M Laimon, YN Khivansara, V Xie, S Durmaz, YT Sarkar, A Ngo, K Savla, V Li, Y Abu-Remaileh, M Li, X Tuladhar, B Odeh, R Hamkins-Indik, F He, D Membreno, MW Nosrati, M Gushwa, NN Leung, SSF Fraga-Walton, B Hernandez, L Baldomero, MP Lent, BM Spellmeyer, D Luna, JF Hoang, D Gritsenko, Y Chand, M DeMart, MK Metobo, S Bhatt, C Shapiro, JA Yang, K Dupper, NJ Bockus, AT Doench, JG Aggen, JB Liu, L-F Levin, B Wang, EW Vendrell, I Fischer, R Kessler, B Gokhale, PC Signoretti, S Spektor, A Kreatsoulas, C Singh, R Earp, DJ Garcia, PD Nijhawan, D Oser, MG |
| author_facet | Singh, S Gleason, CE Fang, M Laimon, YN Khivansara, V Xie, S Durmaz, YT Sarkar, A Ngo, K Savla, V Li, Y Abu-Remaileh, M Li, X Tuladhar, B Odeh, R Hamkins-Indik, F He, D Membreno, MW Nosrati, M Gushwa, NN Leung, SSF Fraga-Walton, B Hernandez, L Baldomero, MP Lent, BM Spellmeyer, D Luna, JF Hoang, D Gritsenko, Y Chand, M DeMart, MK Metobo, S Bhatt, C Shapiro, JA Yang, K Dupper, NJ Bockus, AT Doench, JG Aggen, JB Liu, L-F Levin, B Wang, EW Vendrell, I Fischer, R Kessler, B Gokhale, PC Signoretti, S Spektor, A Kreatsoulas, C Singh, R Earp, DJ Garcia, PD Nijhawan, D Oser, MG |
| author_sort | Singh, S |
| collection | OXFORD |
| description | Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity. |
| first_indexed | 2025-03-11T16:56:49Z |
| format | Internet publication |
| id | oxford-uuid:7d7e29fb-0306-4a4c-b0db-9b000ba713a3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-03-11T16:56:49Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:7d7e29fb-0306-4a4c-b0db-9b000ba713a32025-02-21T15:31:54ZCyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activityInternet publicationhttp://purl.org/coar/resource_type/c_7ad9uuid:7d7e29fb-0306-4a4c-b0db-9b000ba713a3EnglishSymplectic Elements2024Singh, SGleason, CEFang, MLaimon, YNKhivansara, VXie, SDurmaz, YTSarkar, ANgo, KSavla, VLi, YAbu-Remaileh, MLi, XTuladhar, BOdeh, RHamkins-Indik, FHe, DMembreno, MWNosrati, MGushwa, NNLeung, SSFFraga-Walton, BHernandez, LBaldomero, MPLent, BMSpellmeyer, DLuna, JFHoang, DGritsenko, YChand, MDeMart, MKMetobo, SBhatt, CShapiro, JAYang, KDupper, NJBockus, ATDoench, JGAggen, JBLiu, L-FLevin, BWang, EWVendrell, IFischer, RKessler, BGokhale, PCSignoretti, SSpektor, AKreatsoulas, CSingh, REarp, DJGarcia, PDNijhawan, DOser, MGCancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity. |
| spellingShingle | Singh, S Gleason, CE Fang, M Laimon, YN Khivansara, V Xie, S Durmaz, YT Sarkar, A Ngo, K Savla, V Li, Y Abu-Remaileh, M Li, X Tuladhar, B Odeh, R Hamkins-Indik, F He, D Membreno, MW Nosrati, M Gushwa, NN Leung, SSF Fraga-Walton, B Hernandez, L Baldomero, MP Lent, BM Spellmeyer, D Luna, JF Hoang, D Gritsenko, Y Chand, M DeMart, MK Metobo, S Bhatt, C Shapiro, JA Yang, K Dupper, NJ Bockus, AT Doench, JG Aggen, JB Liu, L-F Levin, B Wang, EW Vendrell, I Fischer, R Kessler, B Gokhale, PC Signoretti, S Spektor, A Kreatsoulas, C Singh, R Earp, DJ Garcia, PD Nijhawan, D Oser, MG Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity |
| title | Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity |
| title_full | Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity |
| title_fullStr | Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity |
| title_full_unstemmed | Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity |
| title_short | Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity |
| title_sort | cyclin a b rxl macrocyclic inhibitors to treat cancers with high e2f activity |
| work_keys_str_mv | AT singhs cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT gleasonce cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT fangm cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT laimonyn cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT khivansarav cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT xies cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT durmazyt cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT sarkara cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT ngok cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT savlav cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT liy cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT aburemailehm cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT lix cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT tuladharb cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT odehr cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT hamkinsindikf cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT hed cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT membrenomw cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT nosratim cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT gushwann cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT leungssf cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT fragawaltonb cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT hernandezl cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT baldomeromp cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT lentbm cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT spellmeyerd cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT lunajf cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT hoangd cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT gritsenkoy cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT chandm cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT demartmk cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT metobos cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT bhattc cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT shapiroja cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT yangk cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT duppernj cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT bockusat cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT doenchjg cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT aggenjb cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT liulf cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT levinb cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT wangew cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT vendrelli cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT fischerr cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT kesslerb cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT gokhalepc cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT signorettis cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT spektora cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT kreatsoulasc cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT singhr cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT earpdj cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT garciapd cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT nijhawand cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity AT osermg cyclinabrxlmacrocyclicinhibitorstotreatcancerswithhighe2factivity |