Oncogenic signals prime cancer cells for toxic cell overgrowth during a G1 cell cycle arrest

TY - JOUR

T1 - Oncogenic signals prime cancer cells for toxic cell overgrowth during a G1 cell cycle arrest

AU - Foy, Reece

AU - Crozier, Lisa

AU - Pareri, Aanchal U.

AU - Valverde, Juan Manuel

AU - Ho Park, Ben

AU - Ly, Tony

AU - Saurin, Adrian T.

N1 - Copyright: © 2023 The Authors.

PY - 2023/11/16

Y1 - 2023/11/16

N2 - CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing progression from G1 or inducing genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage, and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.

AB - CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing progression from G1 or inducing genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage, and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.

KW - CDK4/6

KW - oncogenes

KW - cell growth

KW - cell cycle

KW - growth factors

KW - chemotherapy

KW - breast cancer

KW - p53

KW - p21

KW - replication stress

UR - https://www.scopus.com/pages/publications/85176402195

U2 - 10.1016/j.molcel.2023.10.020

DO - 10.1016/j.molcel.2023.10.020

M3 - Article

C2 - 37977117

SN - 1097-2765

VL - 83

SP - 4047-4061.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 22

ER -