| Title: |
Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity |
| Authors: |
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 |
| Publication Year: |
2025 |
| Collection: |
Oxford University Research Archive (ORA) |
| 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. |
| Document Type: |
other/unknown material |
| Language: |
English |
| Relation: |
https://doi.org/10.1101/2024.08.01.605889 |
| DOI: |
10.1101/2024.08.01.605889 |
| Availability: |
https://doi.org/10.1101/2024.08.01.605889; https://ora.ox.ac.uk/objects/uuid:7d7e29fb-0306-4a4c-b0db-9b000ba713a3 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.DE287FF3 |
| Database: |
BASE |