Research Progress on the CDK4/6 Signaling Pathway and Clinical Application of Its Inhibitors in HR+/HER2- Breast Cancer
KunTuo XinCheng Pharmaceutical R&D (Beijing) Co., Ltd., Beijing, China
Kookmin University, South Korea
Abstract
Breast cancer is a common malignant tumor among women worldwide, with the HR+/HER2- subtype (Luminal type) accounting for 60%-70% of all cases. Endocrine therapy has long been the standard treatment for this subtype; however, 30% of patients exhibit primary resistance, and most initial responders develop acquired resistance after treatment, resulting in a significant disease burden. Dysregulation of the cell cycle is a key mechanism underlying endocrine resistance in this subtype. Cyclin-dependent kinases 4/6 (CDK4/6) form a complex with cyclin D, which phosphorylates the retinoblastoma protein (Rb) to relieve its inhibitory effect on E2F transcription factors, thereby promoting G1–S transition. Aberrant activation of this pathway (e.g., cyclin D1 overexpression, CDK6 amplification) is directly associated with endocrine resistance, making CDK4/6 a critical therapeutic target.
Since 2015, CDK4/6 inhibitors represented by palbociclib have been developed. These inhibitors selectively suppress CDK4/6 activity to block Rb phosphorylation, arresting tumor cell cycles at the G0/G1 phase. Clinical studies have confirmed that combining CDK4/6 inhibitors with endocrine therapy (aromatase inhibitors [AIs] or selective estrogen receptor degraders [SERDs]) extends the median progression-free survival (mPFS) of patients with advanced HR+/HER2- breast cancer from 9-14 months (with conventional endocrine therapy alone) to 24-30 months, reducing the risk of disease progression by 40%-50%. This combination regimen has been designated as a Category I recommendation for first-line treatment of advanced HR+/HER2- breast cancer in guidelines issued by authoritative organizations such as the NCCN(2024) [16], ESMO(2024) [17], and CSCO(2024) [18].
Nevertheless, the clinical application of CDK4/6 inhibitors faces new challenges: approximately 30% of patients have primary resistance, and most initially sensitive patients develop secondary resistance 12-36 months after treatment initiation. The mechanisms of resistance are complex, involving Rb loss-of-function, PI3K/AKT pathway activation, and ESR1 mutations, among others. Clinically, there is a lack of reliable predictive biomarkers and standardized post-resistance intervention strategies. This article systematically reviews the characteristics of HR+/HER2- breast cancer, the regulatory mechanism of the CDK4/6 signaling pathway, the clinical value of CDK4/6 inhibitors, and the issue of drug resistance, aiming to provide a theoretical basis for optimizing clinical treatment decisions and overcoming resistance.
Keywords:
CDK4/6 signaling pathway; Cell cycle regulation; HR+/HER2-breast cancer; Cyclin-dependent kinase 4/6 (CDK4/6); Cyclin D; G1–S transitionCopyright Notice & License:
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Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12. PMID: 35020204.
Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, Shi B. Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res. 2015 Sep 15;5(10):2929-43. PMID: 26693050; PMCID: PMC4656721.
Zhang X, Dong X, Guan Y, et al. Research Progress on Epidemiological Trend and Risk Factors of Female Breast Cancer[J]. Cancer Research on Prevention and Treatment, 2021, 48(1): 87-92. doi: 10.3971/j.issn.1000-8578.2021.20.049
Recommended by Breast Cancer Expert Panel. [Guideline for HER2 detection in breast cancer, the 2019 version]. Zhonghua Bing Li Xue Za Zhi. 2019 Mar 8;48(3):169-175. Chinese. doi: 10.3760/cma.j.issn.0529-5807.2019.03.001. PMID: 30831640.
Expert Committee on Rational Drug Use of the National Health Commission. Guidelines for rational drug use in breast cancer[J]. Chinese Journal of Health Informatics and Management, 2019, 16(3): 377-379. (In Chinese)
Tao X, Li T, Gandomkar Z, Brennan PC, Reed WM. Incidence, mortality, survival, and disease burden of breast cancer in China compared to other developed countries. Asia Pac J Clin Oncol. 2023 Dec;19(6):645-654. doi: 10.1111/ajco.13958. Epub 2023 Apr 7. PMID: 37026375.
Madaio RA, Spalletta G, Cravello L, Ceci M, Repetto L, Naso G. Overcoming endocrine resistance in breast cancer. Curr Cancer Drug Targets. 2010 Aug;10(5):519-28. doi: 10.2174/156800910791517226. PMID: 20384578.
Pan J, Shang F, Ma R, et al. Research progress on the regulatory mechanisms of cyclins, cyclin-dependent kinases, and related kinase inhibitors in cell cycle progression[J]. Chinese Journal of Biotechnology, 2023, 39(4): 1525-1547. (In Chinese)
Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, Harbeck N, Castrellon A, Iyer S, Lu DR, Mori A, Gauthier ER, Bartlett CH, Gelmon KA, Slamon DJ. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019 Apr;174(3):719-729. doi: 10.1007/s10549-018-05125-4. Epub 2019 Jan 10. PMID: 30632023; PMCID: PMC6438948.
Bardia A, Jhaveri K, Kalinsky K, Pernas S, Tsurutani J, Xu B, Hamilton E, Im SA, Nowecki Z, Sohn J, Laurentiis M, Jañez NM, Adamo B, Lee KS, Jung KH, Rubovszky G, Tseng LM, Lu YS, Yuan Y, Maxwell MJ, Haddad V, Khan SS, Rugo HS, Pistilli B. TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Future Oncol. 2024 Mar;20(8):423-436. doi: 10.2217/fon-2023-0188. Epub 2023 Jun 30. PMID: 37387213.
Tang H, Ying H, Bai C. Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance[J]. Medical Journal of Peking Union Medical College Hospital, 2020, 11(6): 758-765. DOI: 10.3969/j.issn.1674-9081.2020.06.022
Weinberg RA. The Biology of Cancer (2nd ed.)[M]. New York: W.W. Norton & Company, 2013.
Suski JM, Braun M, Strmiska V, Sicinski P. Targeting cell-cycle machinery in cancer. Cancer Cell. 2021 Jun 14;39(6):759-778. doi: 10.1016/j.ccell.2021.03.010. Epub 2021 Apr 22. PMID: 33891890; PMCID: PMC8206013.
Mandal R, Becker S, Strebhardt K. Targeting CDK9 for Anti-Cancer Therapeutics. Cancers (Basel). 2021 May 1;13(9):2181. doi: 10.3390/cancers13092181. PMID: 34062779; PMCID: PMC8124690.
Min M, Rong Y, Tian C, Spencer SL. Temporal integration of mitogen history in mother cells controls proliferation of daughter cells. Science. 2020 Jun 12;368(6496):1261-1265. doi: 10.1126/science.aay8241. Epub 2020 Apr 2. PMID: 32241885; PMCID: PMC8363187.
Gradishar WJ, Moran MS, Abraham J, et al. Breast Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2024 Jul;22(5):331-357. doi: 10.6004/jnccn.2024.0035. PMID: 39019058.
Loibl S, André F, Bachelot T, et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2024 Feb;35(2):159-182. doi: 10.1016/j.annonc.2023.11.016. Epub 2023 Dec 13. PMID: 38101773.
Li J, Hao C, Wang K, et al. Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines 2024. Transl Breast Cancer Res. 2024 Jul 25;5:18. doi: 10.21037/tbcr-24-31. PMID: 39184927; PMCID: PMC11341997.
