Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors - Nature

"In G1, unphosphorylated pRB represses activating E2Fs (E2F1-E2F3)17,18. Phosphorylation by CDK4 and CDK6 (CDK4/6)-cyclin D and CDK2-cyclin A/E inhibits this repression, allowing E2F-driven S-phase entry18. Various cancers deregulate the G1-S checkpoint through genomic alterations of different components of the pRB-E2F pathway including inactivation of RB1 or CDKN2A, or amplifications of cyclin D or cyclin E2,3. Although activating E2Fs are necessary for cellular proliferation, too much E2F activity paradoxically induces apoptosis4,5,6,7,8,9, suggesting a Goldilocks phenomenon. E2F1 is further negatively regulated by phosphorylation during S phase through cyclin A-CDK2, which limits its DNA binding."

"Studies from budding yeast to mammalian cells demonstrated that cyclin substrate specificity is determined by a hydrophobic patchon cyclins recognizing short linear motifs on cyclin target proteins. The most well-studied linear motif is the RxL motif, but additional motifs include the LxF, NLxxxL and PxF motifs22,23,24. The hydrophobic patch of cyclin A recognizes and binds to an RxL motif on E2F1 to initiate cyclin A-CDK2-mediated E2F phosphorylation10,14. Disrupting this interaction using tool peptides induces apoptosis selectively in cells with deregulated pRB and increased E2F activity15."

Small cell lung cancer (SCLC) is an aggressive subtype defined by near-universal loss-of-function mutations in RB1 and TP53 and lacks recurrent druggable oncogenic drivers. pRB represses activating E2Fs in G1, and phosphorylation by CDK4/6–cyclin D and CDK2–cyclin A/E releases E2F-driven S-phase entry. Deregulation of the pRB–E2F pathway through RB1 loss, CDKN2A inactivation, or cyclin amplifications drives proliferation, while excessive E2F activity induces apoptosis, indicating a Goldilocks balance. Cyclin substrate specificity relies on cyclin hydrophobic patches recognizing linear motifs such as RxL on E2F1 to enable cyclin A–CDK2 phosphorylation. Disrupting the cyclin A–E2F1 interaction can selectively trigger apoptosis in pRB-deregulated cells, though small-molecule inhibitors face challenges and macrocyclic peptides often lack drug-like properties.

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