CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

• DOI: 10.1016/j.molcel.2023.10.016
• Publication Date: 2023-11-16T15:36:13Z
• Authors: Lisa Crozier; Reece Foy; Rozita Adib; Ananya Kar; Jordan A. Holt; Aanchal U. Pareri; Juan M. Valverde; Rene Rivera; William A. Weston; Rona Wilson; Clement Regnault; Phil Whitfield; Mihaly Badonyi; Laura G. Bennett; Ellen G. Vernon; Amelia Gamble; Joseph A. Marsh; Christopher J. St...; Adrian T. Saurin; Alexis R. Barr; Tony Ly
• Keywords: Senescence; Osmotic shock; Replication

Abnormal increases in cell size are associated with senescence and cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the remain unknown. We address this question using CDK4/6 inhibitors, arrest G0/G1 licensed treat advanced HR+/HER2- breast cancer. demonstrate that CDK4/6-inhibited overgrow during G0/G1, causing p38/p53/p21-dependent withdrawal. Cell withdrawal is triggered biphasic p21 induction. first wave caused osmotic stress, leading p38- size-dependent accumulation of p21. inhibitor washout results some entering S-phase. Overgrown experience replication resulting a second promotes G2 or subsequent G1. propose levels integrate signals overgrowth-triggered stresses determine fate. This model explains how hypertrophy can drive why inhibitors have long-lasting effects patients.