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

ABSTRACT: Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1-S checkpoint and leading to dysregulated E2F activity¹. Other cancers similarly disrupt the G1-S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity^2,3. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis^4-9, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs^10-13. Cyclin A represses E2F through an RxL-dependent interaction^10,14, which, when disrupted, hyperactivates E2F¹⁵. However, this substrate interfac

SUBMITTER: Singh S 

PROVIDER: S-EPMC12527934 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature