Cyclin A/B RxL macrocyclic inhibitors to treat cancers with high E2F activity

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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Dades bibliogràfiques
Autors principals: 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
Format: Internet publication
Idioma:English
Publicat: 2024
Descripció
Sumari: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.

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