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. 2024 Nov 11;42(11):1919-1935.e9.
doi: 10.1016/j.ccell.2024.09.009. Epub 2024 Oct 10.

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

Rei Kudo  1 , Anton Safonov  2 , Catherine Jones  3 , Enrico Moiso  4 , Jonathan R Dry  5 , Hong Shao  3 , Sharanya Nag  3 , Edaise M da Silva  6 , Selma Yeni Yildirim  6 , Qing Li  3 , Elizabeth O'Connell  3 , Payal Patel  3 , Marie Will  7 , Atsushi Fushimi  8 , Marimar Benitez  9 , Martina Bradic  9 , Li Fan  10 , Harikrishna Nakshatri  11 , Dhivya R Sudhan  12 , Christopher R Denz  12 , Iker Huerga Sanchez  5 , Jorge S Reis-Filho  6 , Shom Goel  13 , Andrew Koff  9 , Britta Weigelt  6 , Qamar J Khan  14 , Pedram Razavi  15 , Sarat Chandarlapaty  16
Affiliations
Free article

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

Rei Kudo et al. Cancer Cell. .
Free article

Erratum in

  • Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion.
    Kudo R, Safonov A, Jones C, Moiso E, Dry JR, Shao H, Nag S, da Silva EM, Yildirim SY, Li Q, O'Connell E, Patel P, Will M, Fushimi A, Benitez M, Bradic M, Fan L, Nakshatri H, Sudhan DR, Denz CR, Reis-Filho JS, Goel S, Koff A, Weigelt B, Khan QJ, Razavi P, Chandarlapaty S. Kudo R, et al. Cancer Cell. 2024 Nov 11;42(11):1983. doi: 10.1016/j.ccell.2024.10.013. Cancer Cell. 2024. PMID: 39532066 No abstract available.

Abstract

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 large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can 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.

Keywords: CDK2; CDK4/6; breast cancer; cell cycle; cyclin dependent kinase; drug resistance; p53; quiescence; senescence.

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Conflict of interest statement

Declaration of interests 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, and has shares in Totus Medicines. A.K. is a founder of Atropos Therapeutics and has received research support from Lilly. P.R. has received institutional grant/funding from Grail, Novartis, AstraZeneca, EpicSciences, Invitae/ArcherDx, Biothernostics, Tempus, Neogenomics, Biovica, Guardant, Personalis, Myriad and consultation/Ad board/Honoraria from Novartis, AstraZeneca, Pfizer, Lilly/Loxo, Prelude Therapeutics, Epic Sciences, Daiichi-Sankyo, Foundation Medicine, Inivata, Natera, Tempus, SAGA Diagnostics, Paige.ai, Guardant, and Myriad. 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. J.S.R.-F., D.R.S., and C.R.D. were paid employees and/or owned stock of AstraZeneca. J.R.D. and I.H.S were paid employees and/or owned stock of Tempus. I.H.S. is an advisor and has received compensation and stock options from Immunai and Weave.

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