AccScience Publishing / TD / Online First / DOI: 10.36922/td.7107
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REVIEW ARTICLE

Cyclin-dependent kinase 4/6 inhibitor resistance mechanisms and strategies for subsequent treatment in breast cancer: A comprehensive review

Yuling Zhang1 ,  Bingfeng Chen2 ,  Rendong Zhang2 ,  Jundong Wu2,3* ,  Chunfa Chen2,3*
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1 Department of Medical Quality Management, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, China
2 The Breast Center, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, China
3 The Research Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, China
Tumor Discovery, 7107 https://doi.org/10.36922/td.7107
Submitted: 8 December 2024 | Revised: 8 January 2025 | Accepted: 14 January 2025 | Published: 5 February 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the therapeutic landscape for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, demonstrating significant efficacy in both early and advanced stages of the disease. Combined with endocrine therapy, these inhibitors have dramatically improved survival outcomes. However, resistance to CDK4/6 inhibitors inevitably develops, posing a significant challenge in clinical management. Resistance to CDK4/6 inhibitors can develop through inherent and acquired fashions, and their mechanisms are explored in this comprehensive review. Inherent resistance arises from pre-existing genetic or signaling pathway alterations that diminish cancer cell sensitivity to CDK4/6 inhibitors. Acquired resistance, on the other hand, develops over time through mechanisms, such as the activation of alternative signaling pathways or changes in the tumor microenvironment. The review also examines potential biomarkers for predicting resistance, especially circulating tumor DNA markers, and discusses strategies to overcome resistance. These include combination therapies targeting multiple pathways simultaneously, sequential approaches to delay the onset of resistance, and the development of next-generation CDK4/6 inhibitors with improved efficacy and reduced resistance potential. Understanding resistance mechanisms and developing effective countermeasures are crucial for optimizing patient outcomes and extending the clinical benefits of CDK4/6 inhibitors in cancer therapy. Leveraging these insights will enable clinicians to personalize treatment strategies, ultimately enhancing the long-term effectiveness of CDK4/6 inhibitors in managing breast cancer.

Keywords
CDK4/6 inhibitors
Endocrine resistance
Breast cancer
Drug resistance mechanisms
Treatment strategies
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi: 10.3322/caac.21834

 

  1. Dar H, Johansson A, Nordenskjold A, et al. Assessment of 25-year survival of women with estrogen receptor-positive/ ERBB2-negative breast cancer treated with and without tamoxifen therapy: A secondary analysis of data from the stockholm tamoxifen randomized clinical trial. JAMA Netw Open. 2021;4(6):e2114904. doi: 10.1001/jamanetworkopen.2021.14904

 

  1. Chua AV Jr., Sheng H, Liang E, et al. Epidemiology of early vs late recurrence among women with early stage estrogen receptor-positive breast cancer in the Pathways Study. J Natl Cancer Inst. 2024;116(10):1621-31. doi: 10.1093/jnci/djae128

 

  1. Wang X, Zhao S, Xin Q, Zhang Y, Wang K, Li M. Recent progress of CDK4/6 inhibitors’ current practice in breast cancer. Cancer Gene Ther. 2024;31(9):1283-1291. doi: 10.1038/s41417-024-00747-x

 

  1. Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: Mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3(1):39-55. doi: 10.1016/j.trecan.2016.11.006

 

  1. Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: Results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol. 2024;42(9):987-993. doi: 10.1200/JCO.23.01994

 

  1. Hortobagyi GN, Lacko A, Sohn J, et al. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2024;36(2):149-157. doi: 10.1016/j.annonc.2024.10.015

 

  1. Li H, Wu Y, Zou H, et al. Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2- low-positive metastatic breast cancer: A secondary analysis of PALOMA-2 and PALOMA-3 trials. EBioMedicine. 2024;105:105186. doi: 10.1016/j.ebiom.2024.105186

 

  1. Lu YS, Im SA, Colleoni M, et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- advanced breast cancer in MONALEESA-7: A phase III randomized clinical trial. Clin Cancer Res. 2022;28(5):851-859. doi: 10.1158/1078-0432.CCR-21-3032

 

  1. Neven P, Fasching PA, Chia S, et al. Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2- advanced breast cancer receiving first-line ribociclib plus fulvestrant. Breast Cancer Res. 2023;25(1):103. doi: 10.1186/s13058-023-01701-9

 

  1. Goetz MP, Toi M, Huober J, et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol. 2024;35(8):718-727. doi: 10.1016/j.annonc.2024.04.013

 

  1. Xu XQ, Pan XH, Wang TT, et al. Intrinsic and acquired resistance to CDK4/6 inhibitors and potential overcoming strategies. Acta Pharmacol Sin. 2021;42(2):171-178. doi: 10.1038/s41401-020-0416-4

 

  1. Xue Y, Zhai J. Strategy of combining CDK4/6 inhibitors with other therapies and mechanisms of resistance. Int J Clin Exp Pathol. 2024;17(7):189-207. doi: 10.62347/HGNI4903

 

  1. Du Q, Guo X, Wang M, Li Y, Sun X, Li Q. The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J Hematol Oncol. 2020;13(1):41. doi: 10.1186/s13045-020-00880-8

 

  1. Watt AC, Goel S. Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer. Breast Cancer Res. 2022;24(1):17. doi: 10.1186/s13058-022-01510-6

 

  1. George MA, Qureshi S, Omene C, Toppmeyer DL, Ganesan S. Clinical and pharmacologic differences of CDK4/6 inhibitors in breast cancer. Front Oncol. 2021;11:693104. doi: 10.3389/fonc.2021.693104

 

  1. Pandey K, An HJ, Kim SK, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review. Int J Cancer. 2019;145(5):1179-1188. doi: 10.1002/ijc.32020

 

  1. Chen X, Shen K. Dalpiciclib in advanced breast cancer. Lancet Oncol. 2023;24(6):578-579. doi: 10.1016/S1470-2045(23)00228-0

 

  1. Huang J, Zheng L, Sun Z, Li J. CDK4/6 inhibitor resistance mechanisms and treatment strategies (Review). Int J Mol Med. 2022;50(4):128. doi: 10.3892/ijmm.2022.5184

 

  1. Chang CM, Lam HYP. Mechanism of CDK4/6 inhibitor resistance in hormone receptor-positive breast cancer and alternative treatment strategies. Anticancer Res. 2023;43(12):5283-5298. doi: 10.21873/anticanres.16732

 

  1. Zhou FH, Downton T, Freelander A, Hurwitz J, Caldon CE, Lim E. CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective. Front Cell Dev Biol. 2023;11:1148792. doi: 10.3389/fcell.2023.1148792

 

  1. Wander SA, Cohen O, Gong X, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer. Cancer Discov. 2020;10(8):1174-1193. doi: 10.1158/2159-8290.CD-19-1390

 

  1. Lelliott EJ, Sheppard KE, McArthur GA. Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: Is timing everything? NPJ Precis Oncol. 2022;6(1):26. doi: 10.1038/s41698-022-00273-9

 

  1. Sun M, Dong L, Wang Y, et al. The role of targeting CDK4/6 in cancer immunotherapy. Holistic Integr Oncol. 2024;3(1):32. doi: 10.1007/s44178-024-00100-0

 

  1. Teh JLF, Aplin AE. Arrested developments: CDK4/6 inhibitor resistance and alterations in the tumor immune microenvironment. Clin Cancer Res. 2019;25(3):921-927. doi: 10.1158/1078-0432.CCR-18-1967

 

  1. Deng J, Wang ES, Jenkins RW, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8(2):216-233. doi: 10.1158/2159-8290.CD-17-0915

 

  1. Chin YM, Shibayama T, Chan HT, et al. Serial circulating tumor DNA monitoring of CDK4/6 inhibitors response in metastatic breast cancer. Cancer Sci. 2022;113(5):1808-1820. doi: 10.1111/cas.15304

 

  1. Krasniqi E, Goeman F, Pulito C, et al. Biomarkers of response and resistance to CDK4/6 inhibitors in breast cancer: Hints from liquid biopsy and microRNA exploration. Int J Mol Sci. 2022;23(23):14534. doi: 10.3390/ijms232314534

 

  1. Goetz MP, Hamilton EP, Campone M, et al. Landscape of baseline and acquired genomic alterations in circulating tumor DNA with abemaciclib alone or with endocrine therapy in advanced breast cancer. Clin Cancer Res. 2024;30(10):2233-2244. doi: 10.1158/1078-0432.CCR-22-3573

 

  1. Asghar US, Kanani R, Roylance R, Mittnacht S. Systematic review of molecular biomarkers predictive of resistance to CDK4/6 inhibition in metastatic breast cancer. JCO Precis Oncol. 2022;6:e2100002. doi: 10.1200/PO.21.00002

 

  1. Kindt CK, Alves CL, Ehmsen S, et al. Genomic alterations associated with resistance and circulating tumor DNA dynamics for early detection of progression on CDK4/6 inhibitor in advanced breast cancer. Int J Cancer. 2024;155(12):2211-2222. doi: 10.1002/ijc.35126.

 

  1. Davis AA, Luo J, Zheng T, et al. Genomic complexity predicts resistance to endocrine therapy and CDK4/6 inhibition in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer. Clin Cancer Res. 2023;29(9):1719-1729. doi: 10.1158/1078-0432.CCR-22-2177.

 

  1. Li Z, Zou W, Zhang J, et al. Mechanisms of CDK4/6 inhibitor resistance in luminal breast cancer. Front Pharmacol. 2020;11:580251. doi: 10.3389/fphar.2020.580251

 

  1. Yoshida A, Lee EK, Diehl JA. Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended inhibition of CDK4/6. Cancer Res. 2016;76(10):2990-3002. doi: 10.1158/0008-5472.CAN-15-2931

 

  1. Hirai N, Hatanaka Y, Hatanaka KC, et al. Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer. Transl Lung Cancer Res. 2021;10(9):3737-3744. doi: 10.21037/tlcr-21-415

 

  1. Nassar KW, Hintzsche JD, Bagby SM, et al. Targeting CDK4/6 represents a therapeutic vulnerability in acquired BRAF/MEK inhibitor-resistant melanoma. Mol Cancer Ther. 2021;20(10):2049-2060. doi: 10.1158/1535-7163.MCT-20-1126

 

  1. Lelliott EJ, McArthur GA, Oliaro J, Sheppard KE. Immunomodulatory effects of BRAF, MEK, and CDK4/6 inhibitors: Implications for combining targeted therapy and immune checkpoint blockade for the treatment of melanoma. Front Immunol. 2021;12:661737. doi: 10.3389/fimmu.2021.661737

 

  1. Cheng K, Zhou Z, Chen Q, et al. CDK4/6 inhibition sensitizes MEK inhibition by inhibiting cell cycle and proliferation in pancreatic ductal adenocarcinoma. Sci Rep. 2024;14(1):8389. doi: 10.1038/s41598-024-57417-z

 

  1. Sonke GS, van Ommen-Nijhof A, Wortelboer N, et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024;636:474-480. doi: 10.1038/s41586-024-08035-2

 

  1. Wells CI, Vasta JD, Corona CR, et al. Quantifying CDK inhibitor selectivity in live cells. Nat Commun. 2020;11(1):2743. doi: 10.1038/s41467-020-16559-0

 

  1. Bidard FC, Hardy-Bessard AC, Dalenc F, et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): A randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022;23(11):1367-1377. doi: 10.1016/S1470-2045(22)00555-1

 

  1. Ye M, Xu H, Ding J, Jiang L. Therapy for hormone receptor-positive, human epidermal growth receptor 2-negative metastatic breast cancer following treatment progression via CDK4/6 inhibitors: A literature review. Breast Cancer (Dove Med Press). 2024;16:181-197. doi: 10.2147/BCTT.S438366

 

  1. Müller VJE. Current and upcoming treatment strategies after CDK4/6 inhibitors for patients with ER+/HER2- advanced. Breast Cancer. 2023;11(1):33-43.

 

  1. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast Cancer: MAINTAIN trial. J Clin Oncol. 2023;41(24):4004-4013. doi: 10.1200/JCO.22.02392

 

  1. Ma J, Chan JJ, Toh CH, Yap YS. Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer. NPJ Breast Cancer. 2023;9(1):74. doi: 10.1038/s41523-023-00578-3

 

  1. Mittal A, Molto Valiente C, Tamimi F, et al. Filling the gap after CDK4/6 inhibitors: Novel endocrine and biologic treatment options for metastatic hormone receptor positive breast cancer. Cancers (Basel). 2023;15(7):2015. doi: 10.3390/cancers15072015

 

  1. Benvenuti C, Gaudio M, Jacobs F, et al. Clinical review on the management of breast cancer visceral crisis. Biomedicines. 2023;11(4):1083. doi: 10.3390/biomedicines11041083

 

  1. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391:2110-2122. doi: 10.1056/NEJMoa2407086

 

  1. McCartney A, Migliaccio I, Bonechi M, et al. Mechanisms of resistance to CDK4/6 inhibitors: Potential implications and biomarkers for clinical practice. Front Oncol. 2019;9:666. doi: 10.3389/fonc.2019.00666

 

  1. Johnston S, Emde A, Barrios C, et al. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors: Existing and emerging differences. JNCI Cancer Spectr. 2023;7(4):pkad045. doi: 10.1093/jncics/pkad045

 

  1. Thill M, Schmidt M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Ther Adv Med Oncol. 2018;10:1758835918793326. doi: 10.1177/1758835918793326

 

  1. Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: In-vivo cell cycle-dependent/independent anti-tumor activities alone/ in combination with gemcitabine. Invest New Drugs. 2014;32(5):825-837. doi: 10.1007/s10637-014-0120-7

 

  1. Xu B, Zhang Q, Zhang P, et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2- negative advanced breast cancer: A randomized, phase 3 trial. Nat Med. 2021;27(11):1904-1909. doi: 10.1038/s41591-021-01562-9

 

  1. Sheikh MS, Satti SA. The emerging CDK4/6 inhibitor for breast cancer treatment. Mol Cell Pharmacol. 2021;13(3):9-12.

 

  1. Long F, He Y, Fu H, et al. Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models. Cancer Sci. 2019;110(4):1420-1430. doi: 10.1111/cas.13957

 

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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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