Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a clinically-annotated cohort of patients with metastatic HR+ breast cancer, we identified TP53 loss (28.8%) and MDM2 amplification (6.7%) to be associated with lack of long-term disease control. Human breast cancer models revealed that p53 loss did not affect CDK4/6 activity or G1-blockade, but instead promoted drug-insensitive p130 phosphorylation by CDK2. Persistence of phospho-p130 prevented DREAM complex assembly, enabling cell cycle reentry and tumor progression. Inhibitors of CDK2 could overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically-diverse HR+ breast cancers. ### Competing Interest Statement S.C. has received research support and clinical trial support (funding to institution) from Daiichi-Sankyo, Novartis, Sanofi, AstraZeneca, Ambrx, Paige.ai, and Lilly, has received consulting honoraria from Novartis, Paige.ai, AstraZeneca, Boxer Capital, and Lilly, is co-founder and board member of Odyssey Biosciences and has shares in Totus Medicines. A.K. is a founder of Atropos Therapeutics and has received research support from Lilly. J.S.R.-F. reports personal/consultancy fees from VolitionRx, Page.AI, Goldman Sachs, Grail, Ventana Medical Systems, Roche, Genentech, and Invicro. P.R. received institutional grant/funding from Grail, Illumina, Novartis, AstraZeneca, Epic Sciences, Invitae/ArcherDx, Tempus, Inivata, Guardant and consultation/Ad board/honoraria from Novartis, Foundation Medicine, AstraZeneca, Pfizer, Epic Sciences, Inivata, Natera, Tempus, Biovica, Saga and is co-founder and board member at Odyssey Biosciences. S.G. reports receipt of laboratory research funding from Eli Lilly and G1 Therapeutics and receipt of honoraria for advisory work from Eli Lilly, G1 Therapeutics, and Pfizer. B.W. reports grant funding by Repare Therapeutics. The remaining authors declare no competing interests.