Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion PMID: 39393354

ADC Targets in Oncology

2026-04-10

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

Cancer Cell. 2024 Nov 11;42(11):1919-1935.e9. doi: 10.1016/j.ccell.2024.09.009.

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

1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSK), New York, NY 10065, USA; Department of Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan.
2. Breast Medicine Service, Department of Medicine, MSK, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSK), New York, NY 10065, USA.
4. Department of Medicine, MSK, New York, NY 10065, USA; Department of Epidemiology and Biostatistics, MSK, New York, NY 10065, USA.
5. Tempus AI, Boston, MA 02110, USA.
6. Department of Pathology and Laboratory Medicine, MSK, New York, NY 10065, USA.
7. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSK), New York, NY 10065, USA; Breast Medicine Service, Department of Medicine, MSK, New York, NY 10065, USA; Clinical Genetics Service, Department of Medicine, MSK, New York, NY 10065, USA.
8. Department of Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan.
9. Program in Molecular Biology, Sloan Kettering Institute, MSK, New York, NY 10065, USA.
10. Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA.
11. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
12. Oncology R&D, AstraZeneca, Waltham, MA 02451, USA.
13. Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia.
14. Division of Medical Oncology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
15. Breast Medicine Service, Department of Medicine, MSK, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: [email protected].
16. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSK), New York, NY 10065, USA; Breast Medicine Service, Department of Medicine, MSK, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: [email protected].

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.