| Autor: |
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 LF, 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 |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 01. Date of Electronic Publication: 2024 Aug 01. |
| DOI: |
10.1101/2024.08.01.605889 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
