tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2026-067tumors-1630Research ArticleОБЗОРЫ И АНАЛИТИКАREVIEWS AND ANALYSISМеханизмы регуляции клеточного цикла CDK4 / 6 и пути формирования устойчивости к их ингибиторам (литературный обзор)Mechanisms of cell cycle regulation by CDK4 / 6 and pathways for the formation of resistance to their inhibitors (literature review)https://orcid.org/0009-0009-5838-6202КуцебкоД. Н.KutsebkoD. N.

Дарья Николаевна Куцебко

194044 Санкт-Петербург, ул. Академика Лебедева, 6

Daria Nikolaevna Kutsebko

6, Akademika Lebedeva St., 194044 Saint Petersburg

heyiamdi@gmail.comhttps://orcid.org/0000-0002-0161-5977ГлушаковР. И.GlushakovR. I.

Руслан Иванович Глушаков

194044 Санкт-Петербург, ул. Академика Лебедева, 6

Ruslan Ivanovich Glushakov

6, Akademika Lebedeva St., 194044 Saint Petersburg

ФГБВОУ ВО «Военно-медицинская академия им. С. М. Кирова» Министерства обороны РФРоссияMilitary Medical Academy named after S. M. KirovRussian Federation20262104202616182–97Copyright © Куцебко Д.Н., Глушаков Р.И., 20262026Куцебко Д.Н., Глушаков Р.И.Kutsebko D.N., Glushakov R.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.malignanttumors.org/jour/article/view/1630

Ингибиторы циклинзависимых киназ (CDK4 / 6i) вошли в стандарт лечения гормон-рецептор-положительного (HR+) / HER2‑отрицательного (HER2–) рака молочной железы (РМЖ), однако их эффективность у большинства пациентов оказывается временной. Приобретенная резистентность — это не исключение, а правило, которое становится главным препятствием на пути к долгосрочному контролю над онкологическим заболеванием. Для анализа современных данных о механизмах резистентности был проведён поиск и анализ публикаций в базах данных PubMed / MEDLINE, Scopus и Web of Science за период 2015–2024 гг., включая основополагающие работы предыдущих лет. В данном обзоре систематизированы актуальные данные о молекулярных механизмах лекарственной резистентности к CDK4 / 6i. Представлены данные по нарушению регуляции клеточного цикла, активации компенсаторных внутриклеточных сигнальных каскадов, позволяющих опухолевым клеткам нивелировать эффект действия противоопухолевого агента.

Основные варианты резистентности к CDK4 / 6i включают в себя изменение экспрессии самих циклинзависимых киназ (гиперэкспрессия CDK6 или снижение CDK4), потерю или снижение экспрессии рецептора к эстрогену (ER), нарушение функции белка ретинобластомы (Rb), а также утрату ко-активатора APC / C-FZR1, приводящую к дисфункции комплекса APC / CMR1 и гиперактивации CDK. Особый интерес представляет амплификация гена CDKN2A, являющегося супрессором опухолевого роста, при которой происходит изменения функциональных свойств коди‑ руемого данным генов белка p16^INK4a, приобретающего неканонические онкогенные функции.

Существенный вклад в развитие резистентности вносят и альтернативные сигнальные пути: гиперактивация PI3K — AKT — mTOR, активация FGFR, дисрегуляция сигнального пути протеинкиназы Hippo. Гиперактивация PI3K — AKT — mTOR, часто коррелирующая с утратой белка-онкосупрессора PTEN, ассоциирована не только с устойчивостью к CDK4 / 6i, но и со снижением эффективности PI3K — ингибиторов. Активация FGFR стимулирует сигналинг MAPK- и PI3K-каскадов и обеспечивает лиганд-независимую активацию ER за счет протеинового фосфорилирования. Дисрегуляция пути Hippo ведёт к ядерной транслокации YAP / TAZ и усилению экспрессии генов пролиферации, включая CDK6. Такое многообразие механизмов резистентности делает терапию своеобразной игрой в “whack-a-mole”: подавление одного механизма неизбежно сопровождается активацией альтернативных. Преодоление резистентности диктует необходимость разработки комбинированных стратегий, направленных на синергичное ингибирование как канонического пути пролиферации, так и критических компенсаторных каскадов. Подобный подход открывает перспективы для создания персонализированной терапии для пациентов с HR+ / (HER2–) РМЖ.

Cyclin-dependent kinase 4 / 6 inhibitors (CDK4 / 6i) have become a standard component of therapy for hormone receptor — positive (HR+) / HER2‑negative (HER2–) breast cancer (BC). However, in most patients, their clinical benefit is only temporary. Acquired resistance is not the exception but the rule, representing a major barrier to achieving durable disease control. To summarize current knowledge on resistance mechanisms, we conducted a literature search and analysis in the PubMed / MEDLINE, Scopus, and Web of Science databases covering the period 2015–2024, supplemented by seminal publications from earlier years.

This review summarizes current evidence on the molecular mechanisms underlying resistance to CDK4 / 6 inhibitors. It highlights alterations in cell-cycle regulation and activation of compensatory intracellular signaling cascades that enable tumor cells to circumvent the effects of these agents.

The principal mechanisms of resistance to CDK4 / 6i include altered expression of the kinases themselves (CDK6 overexpression or CDK4 downregulation), loss or reduced expression of the estrogen receptor (ER), dysfunction of the retinoblastoma protein (Rb), and loss of the APC / C co-activator FZR1, leading to APC / CMR1 complex dysfunction and CDK hyperactivation. Of particular interest is amplification of the CDKN2A tumor-suppressor gene, which alters the functional properties of its product, p16^INK4a, endowing it with noncanonical oncogenic activity. Alternative signaling pathways also play key roles in resistance development, including hyperactivation of PI3K — AKT — mTOR, activation of FGFR, and dysregulation of the Hippo kinase pathway. PI3K — AKT — mTOR hyperactivation, often associated with loss of the tumor suppressor PTEN, correlates not only with resistance to CDK4 / 6i but also with reduced sensitivity to PI3K inhibitors. FGFR activation stimulates MAPK and PI3K signaling cascades and promotes ligand-independent ER activation through protein phosphorylation. Dysregulation of the Hippo pathway drives nuclear translocation of YAP / TAZ and enhances expression of proliferation-related genes, including CDK6. The diversity of these resistance mechanisms turns therapy into a “whack-a-mole” scenario: inhibition of one pathway inevitably triggers activation of another. Overcoming resistance therefore requires the development of rational combination strategies that synergistically target both the canonical proliferation pathway and critical compensatory cascades. Such an approach holds promise for the development of truly personalized therapies for patients with HR+ / (HER2–) breast cancer.

рак молочной железырезистентность к CDK4 / 6iHR+ / (HER2–) РМЖмеханизмы резистентностиCDK4CDK6белок ретинобластомы (Rb)сигнальный путь PI3K — AKT — mTORbreast cancerCDK4 / 6i resistanceHR+ / (HER2–) breast cancerdrug resistance mechanismsCDK4CDK6Rb proteinPI3K — AKT — mTOR signalingReferencesBreast cancer. World Health Organization (WHO). Available at: https://www.who.int/news-room/fact-sheets/detail/breast-cancerBreast cancer. World Health Organization (WHO). Available at: https://www.who.int/news-room/fact-sheets/detail/breast-cancerFemale Breast Cancer Subtypes. SEER Cancer Stat Facts. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.htmlFemale Breast Cancer Subtypes. SEER Cancer Stat Facts. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.htmlSotiriou C., Pusztai L. Gene-Expression Signatures in Breast Cancer. N Engl J Med 2009;360(8):790–800. https://doi.org/10.1056/NEJMra0801289Sotiriou C., Pusztai L. Gene-Expression Signatures in Breast Cancer. N Engl J Med 2009;360(8):790–800. https://doi.org/10.1056/NEJMra0801289Ignatiadis M., Sotiriou C. Luminal breast cancer: from biology to treatment. Nat Rev Clin Oncol 2013;10(9):494–506. https://doi.org/110.1038/nrclinonc.2013.123Ignatiadis M., Sotiriou C. Luminal breast cancer: from biology to treatment. Nat Rev Clin Oncol 2013;10(9):494–506. https://doi.org/110.1038/nrclinonc.2013.123Choi Y.J., Li Y., Hydbring P., et al. The Requirement for cyclin D function in tumor maintenance. Cancer Cell 2012;22(4):438–451. https://doi.org/10.1016/j.ccr.2012.09.015Choi Y.J., Li Y., Hydbring P., et al. The Requirement for cyclin D function in tumor maintenance. Cancer Cell 2012;22(4):438–451. https://doi.org/10.1016/j.ccr.2012.09.015Filmus J., Robles A.I., Shi W., et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 1994;9(12):3627–3633Filmus J., Robles A.I., Shi W., et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 1994;9(12):3627–3633Ribnikar D., Volovat S.R., Cardoso F. Targeting CDK4/6 pathways and beyond in breast cancer. Breast 2019;43:8–17. https://doi.org/10.1016/j.breast.2018.10.001Ribnikar D., Volovat S.R., Cardoso F. Targeting CDK4/6 pathways and beyond in breast cancer. Breast 2019;43:8–17. https://doi.org/10.1016/j.breast.2018.10.001Konecny G.E., Winterhoff B., Kolarova T., et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res 2011;17(6):1591–1602. https://doi.org/10.1158/1078-0432.CCR-10-2307Konecny G.E., Winterhoff B., Kolarova T., et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res 2011;17(6):1591–1602. https://doi.org/10.1158/1078-0432.CCR-10-2307Herrera-Abreu M.T., Palafox M., Asghar U., et al. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer. Cancer Res 2016;76(8):2301–2313. https://doi.org/10.1158/0008-5472. CAN-15-0728Herrera-Abreu M.T., Palafox M., Asghar U., et al. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer. Cancer Res 2016;76(8):2301–2313. https://doi.org/10.1158/0008-5472. CAN-15-0728Malumbres M., Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009;9(3):153–166. https://doi.org/10.1038/nrc2602Malumbres M., Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009;9(3):153–166. https://doi.org/10.1038/nrc2602Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013Nurse P. Regulation of the eukaryotic cell cycle. Eur J Cancer 1997;33(7):1002–1004. https://doi.org/10.1016/S0959-8049(97)00067-2Nurse P. Regulation of the eukaryotic cell cycle. Eur J Cancer 1997;33(7):1002–1004. https://doi.org/10.1016/S0959-8049(97)00067-2Besson A., Dowdy S.F., Roberts J.M. CDK inhibitors: cell cycle regulators and beyond. Dev Cell 2008;14(2):159–169. https://doi.org/10.1016/j.devcel.2008.01.013Besson A., Dowdy S.F., Roberts J.M. CDK inhibitors: cell cycle regulators and beyond. Dev Cell 2008;14(2):159–169. https://doi.org/10.1016/j.devcel.2008.01.013Lee R.J., Albanese C., Fu M., et al. Cyclin D1 is required for transformation by activated neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 2000;20(2):672–683. https://doi.org/10.1128/MCB.20.2.672-683.2000Lee R.J., Albanese C., Fu M., et al. Cyclin D1 is required for transformation by activated neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 2000;20(2):672–683. https://doi.org/10.1128/MCB.20.2.672-683.2000Hatakeyama M., Weinberg R.A. The role of RB in cell cycle control. Prog Cell Cycle Res 1995;1:9–19. https://doi.org/10.1007/978-1-4615-1809-9_2Hatakeyama M., Weinberg R.A. The role of RB in cell cycle control. Prog Cell Cycle Res 1995;1:9–19. https://doi.org/10.1007/978-1-4615-1809-9_2Bertoli C., Skotheim J.M., de Bruin R.A.M. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 2013;14(8):518–528. https://doi.org/10.1038/nrm3629Bertoli C., Skotheim J.M., de Bruin R.A.M. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 2013;14(8):518–528. https://doi.org/10.1038/nrm3629Medema R.H., Herrera R.E., Lam F., Weinberg R.A. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A 1995;92(14):6289–6293. https://doi.org/10.1073/pnas.92.14.6289Medema R.H., Herrera R.E., Lam F., Weinberg R.A. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A 1995;92(14):6289–6293. https://doi.org/10.1073/pnas.92.14.6289Nakayama K., Nakayama K. Cip/Kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development. BioEssays 1998;20(12):1020–1029. https://doi.org/10.1002/(SICI)1521-1878(199812)20:12<1020::AIDBIES8>3.0.CO;2-DNakayama K., Nakayama K. Cip/Kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development. BioEssays 1998;20(12):1020–1029. https://doi.org/10.1002/(SICI)1521-1878(199812)20:12<1020::AIDBIES8>3.0.CO;2-DYu Q., Geng Y., Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature. 2001;411(6841):1017– 1021. https://doi.org/10.1038/35082500Yu Q., Geng Y., Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature. 2001;411(6841):1017– 1021. https://doi.org/10.1038/35082500Yu Q., Sicinska E., Geng Y., et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006;9(1):23–32. https://doi.org/10.1016/j.ccr.2005.12.012Yu Q., Sicinska E., Geng Y., et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006;9(1):23–32. https://doi.org/10.1016/j.ccr.2005.12.012Zwijsen R.M., Wientjens E., Klompmaker R., et al. CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997;88(3):405–415. https://doi.org/10.1016/S0092-8674(00)81879-6Zwijsen R.M., Wientjens E., Klompmaker R., et al. CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997;88(3):405–415. https://doi.org/10.1016/S0092-8674(00)81879-6Wu S., Xu J., Ma Y., et al. Advances in the mechanism of CDK4/6 inhibitor resistance in HR+/HER2− breast cancer. Ther Adv Med Oncol 2024;16:17588359241282499. https://doi.org/10.1177/17588359241282499Wu S., Xu J., Ma Y., et al. Advances in the mechanism of CDK4/6 inhibitor resistance in HR+/HER2− breast cancer. Ther Adv Med Oncol 2024;16:17588359241282499. https://doi.org/10.1177/17588359241282499Al-Shami K., Awadi S., Khamees A., et al. Estrogens and the risk of breast cancer: A narrative review of literature. Heliyon 2023;9(9):e20224. https://doi.org/10.1016/j.heliyon.2023.e20224Al-Shami K., Awadi S., Khamees A., et al. Estrogens and the risk of breast cancer: A narrative review of literature. Heliyon 2023;9(9):e20224. https://doi.org/10.1016/j.heliyon.2023.e20224Prall O.W., Rogan E.M., Sutherland R.L. Estrogen regulation of cell cycle progression in breast cancer cells. J Steroid Biochem Mol Biol 1998;65(1–6):169–174. https://doi.org/10.1016/s0960-0760(98)00021-1Prall O.W., Rogan E.M., Sutherland R.L. Estrogen regulation of cell cycle progression in breast cancer cells. J Steroid Biochem Mol Biol 1998;65(1–6):169–174. https://doi.org/10.1016/s0960-0760(98)00021-1Renoir J.M., Marsaud V., Lazennec G. Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol 2013;85(4):449–465. https://doi.org/10.1016/j.bcp.2012.10.018Renoir J.M., Marsaud V., Lazennec G. Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol 2013;85(4):449–465. https://doi.org/10.1016/j.bcp.2012.10.018Muise-Helmericks R.C., Grimes H.L., Bellacosa A., et al. Cyclin D Expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 1998;273(45):29864–29872. https://doi.org/10.1074/jbc.273.45.29864Muise-Helmericks R.C., Grimes H.L., Bellacosa A., et al. Cyclin D Expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 1998;273(45):29864–29872. https://doi.org/10.1074/jbc.273.45.29864Viedma-Rodríguez R., Baiza-Gutman L., Salamanca-Gómez F., et al. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review). Oncology Reports. 2014;32(1):3–15. https://doi.org/10.3892/or.2014.3190Viedma-Rodríguez R., Baiza-Gutman L., Salamanca-Gómez F., et al. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review). Oncology Reports. 2014;32(1):3–15. https://doi.org/10.3892/or.2014.3190Koirala N., Dey N., Aske J., De P. Targeting cell cycle progression in HER2+ breast cancer: an emerging treatment opportunity. Int J Mol Sci 2022;23(12):6547. https://doi.org/10.3892/or.2014.319010.3390/ijms23126547Koirala N., Dey N., Aske J., De P. Targeting cell cycle progression in HER2+ breast cancer: an emerging treatment opportunity. Int J Mol Sci 2022;23(12):6547. https://doi.org/10.3892/or.2014.319010.3390/ijms23126547Hu Y., Gao J., Wang M., Li M. Potential prospect of CDK4/6 inhibitors in triple-negative breast cancer. Cancer Manag Res 2021;13:5223–5237. https://doi.org/10.2147/CMAR.S310649Hu Y., Gao J., Wang M., Li M. Potential prospect of CDK4/6 inhibitors in triple-negative breast cancer. Cancer Manag Res 2021;13:5223–5237. https://doi.org/10.2147/CMAR.S310649Bosco E.E., Knudsen E.S. RB in breast cancer: at the crossroads of tumorigenesis and treatment. Cell Cycle 2007;6(6):667– 671. https://doi.org/10.4161/cc.6.6.3988Bosco E.E., Knudsen E.S. RB in breast cancer: at the crossroads of tumorigenesis and treatment. Cell Cycle 2007;6(6):667– 671. https://doi.org/10.4161/cc.6.6.3988Gelbert L.M., 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. https://doi.org/10.1007/s10637-014-0120-7Gelbert L.M., 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. https://doi.org/10.1007/s10637-014-0120-7Wagner V., Gil J. Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene 2020;39(29):5165– 5176. https://doi.org/10.1038/s41388-020-1354-9Wagner V., Gil J. Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene 2020;39(29):5165– 5176. https://doi.org/10.1038/s41388-020-1354-9Anders L., Ke N., Hydbring P., et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 2011;20(5):620–634. https://doi.org/10.1016/j.ccr.2011.10.001Anders L., Ke N., Hydbring P., et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 2011;20(5):620–634. https://doi.org/10.1016/j.ccr.2011.10.001Acevedo M., Vernier M., Mignacca L., et al. A CDK4/6-dependent epigenetic mechanism protects cancer cells from PML-induced senescence. Cancer Res 2016;76(11):3252–3264. https://doi.org/10.1158/0008-5472.CAN-15-2347Acevedo M., Vernier M., Mignacca L., et al. A CDK4/6-dependent epigenetic mechanism protects cancer cells from PML-induced senescence. Cancer Res 2016;76(11):3252–3264. https://doi.org/10.1158/0008-5472.CAN-15-2347Torres-Guzmán R., Calsina B., Hermoso A., et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget 2017;8(41):69493–69507. https://doi.org/10.18632/oncotarget.17778Torres-Guzmán R., Calsina B., Hermoso A., et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget 2017;8(41):69493–69507. https://doi.org/10.18632/oncotarget.17778Litchfield L.M., Boehnke K., Brahmachary M., et al. Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells. Oncotarget 2020;11(17):1478–1492. https://doi.org/10.18632/oncotarget.27539Litchfield L.M., Boehnke K., Brahmachary M., et al. Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells. Oncotarget 2020;11(17):1478–1492. https://doi.org/10.18632/oncotarget.27539Hafner M., Mills C.E., Subramanian K., et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chem Biol 2019;26(8):1067–1080.e8. https://doi.org/10.1016/j.chembiol.2019.05.005Hafner M., Mills C.E., Subramanian K., et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chem Biol 2019;26(8):1067–1080.e8. https://doi.org/10.1016/j.chembiol.2019.05.005Portman D. Jю, Palmieri A., Anders C.K., et al. CDK4/6 inhibitors in hormone receptor-positive, HER2-negative advanced breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat. 2024;203(1):1–12. PMID: 37889338. https://doi:10.1007/s10549-018-4901-0Portman D. Jю, Palmieri A., Anders C.K., et al. CDK4/6 inhibitors in hormone receptor-positive, HER2-negative advanced breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat. 2024;203(1):1–12. PMID: 37889338. https://doi:10.1007/s10549-018-4901-0Guiley K.Z., Stevenson J.W., Lou K., et al. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition. Science 2019;366(6471):eaaw2106. https://doi.org/10.1126/science.aaw2106Guiley K.Z., Stevenson J.W., Lou K., et al. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition. Science 2019;366(6471):eaaw2106. https://doi.org/10.1126/science.aaw2106Pack L.R., Daigh L.H., Chung M., Meyer T. Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2. Nat Commun 2021;12(1):3356. https://doi.org/10.1038/s41467-021-23612-zPack L.R., Daigh L.H., Chung M., Meyer T. Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2. Nat Commun 2021;12(1):3356. https://doi.org/10.1038/s41467-021-23612-zGuan Y., Zhang L., Lyu G., et al. Senescence-activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fibroblasts. Nucleic Acids Res 2020;48(19):10909–10923. https://doi.org/10.1093/nar/gkaa858Guan Y., Zhang L., Lyu G., et al. Senescence-activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fibroblasts. Nucleic Acids Res 2020;48(19):10909–10923. https://doi.org/10.1093/nar/gkaa858Watt A.C., Cejas P., DeCristo M.J., et al. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity. Nat Cancer 2021;2(1):34–48. https://doi.org/10.1038/s43018-020-00135-yWatt A.C., Cejas P., DeCristo M.J., et al. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity. Nat Cancer 2021;2(1):34–48. https://doi.org/10.1038/s43018-020-00135-yWhittle J.R., Vaillant F., Surgenor E., et al. Dual targeting of CDK4/6 and BCL2 pathways augments tumor response in estrogen receptor–positive breast cancer. Clin Cancer Res 2020;26(15):4120–4134. https://doi.org/10.1158/1078-0432.CCR-19-1872Whittle J.R., Vaillant F., Surgenor E., et al. Dual targeting of CDK4/6 and BCL2 pathways augments tumor response in estrogen receptor–positive breast cancer. Clin Cancer Res 2020;26(15):4120–4134. https://doi.org/10.1158/1078-0432.CCR-19-1872Brown N.E., Jeselsohn R., Bihani T., et al. Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium. Cancer Res 2012;72(24):6477–6489. https://doi.org/10.1158/0008-5472.CAN-11-4139Brown N.E., Jeselsohn R., Bihani T., et al. Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium. Cancer Res 2012;72(24):6477–6489. https://doi.org/10.1158/0008-5472.CAN-11-4139Vijayaraghavan S., Karakas C., Doostan I., et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun 2017;8:15916. https://doi.org/10.1038/ncomms15916Vijayaraghavan S., Karakas C., Doostan I., et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun 2017;8:15916. https://doi.org/10.1038/ncomms15916Yang C., Li Z., Bhatt T., et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 2017;36(16):2255–2264. https://doi.org/10.1038/onc.2016.379Yang C., Li Z., Bhatt T., et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 2017;36(16):2255–2264. https://doi.org/10.1038/onc.2016.379Kollmann K., Heller G., Schneckenleithner C., et al. A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell 2013;24(2):167–181. https://doi.org/10.1016/j.ccr.2013.07.012Kollmann K., Heller G., Schneckenleithner C., et al. A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell 2013;24(2):167–181. https://doi.org/10.1016/j.ccr.2013.07.012Yang C, Li Z, Bhatt T, et al. Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors. Nat Commun. 2025;16:55914. https://doi:10.1038/s41467-025-55914-xYang C, Li Z, Bhatt T, et al. Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors. Nat Commun. 2025;16:55914. https://doi:10.1038/s41467-025-55914-xPatel P., Asbach B., Shteyn E., et al. Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4. Mol Cell Biol 2015;35(9):1506–1522. https://doi.org/10.1128/MCB.01206-14Patel P., Asbach B., Shteyn E., et al. Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4. Mol Cell Biol 2015;35(9):1506–1522. https://doi.org/10.1128/MCB.01206-14Sutherland R.L., Green M.D., Hall R.E., et al. Tamoxifen induces accumulation of MCF 7 human mammary carcinoma cells in the G0/G1 phase of the cell cycle. Eur J Cancer Clin Oncol 1983;19(5):615–621. https://doi.org/10.1016/0277-5379(83)90177-3Sutherland R.L., Green M.D., Hall R.E., et al. Tamoxifen induces accumulation of MCF 7 human mammary carcinoma cells in the G0/G1 phase of the cell cycle. Eur J Cancer Clin Oncol 1983;19(5):615–621. https://doi.org/10.1016/0277-5379(83)90177-3Foster J.S., Henley D.C., Bukovsky A., et al. Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Mol Cell Biol 2001;21(3):794–810. https://doi.org/10.1128/MCB.21.3.794-810.2001Foster J.S., Henley D.C., Bukovsky A., et al. Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Mol Cell Biol 2001;21(3):794–810. https://doi.org/10.1128/MCB.21.3.794-810.2001Du C., Li Z., Wang S., et al. Tongshu capsule down-regulates the expression of estrogen receptor α and suppresses human breast cancer cell proliferation. PLoS One 2014;9(8):e104261. https://doi.org/10.1371/journal.pone.0104261Du C., Li Z., Wang S., et al. Tongshu capsule down-regulates the expression of estrogen receptor α and suppresses human breast cancer cell proliferation. PLoS One 2014;9(8):e104261. https://doi.org/10.1371/journal.pone.0104261Gong X., Litchfield L.M., Webster Y., et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell 2017;32(6):761–776.e6. https://doi.org/10.1016/j.ccell.2017.11.006Gong X., Litchfield L.M., Webster Y., et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell 2017;32(6):761–776.e6. https://doi.org/10.1016/j.ccell.2017.11.006Fribbens C., O’Leary B., Kilburn L., et al. Plasma ESR1 mutations and the treatment of estrogen receptor–positive advanced breast cancer. J Clin Oncol 2016;34(25):2961–2968. https://doi.org/10.1200/JCO.2016.67.3061Fribbens C., O’Leary B., Kilburn L., et al. Plasma ESR1 mutations and the treatment of estrogen receptor–positive advanced breast cancer. J Clin Oncol 2016;34(25):2961–2968. https://doi.org/10.1200/JCO.2016.67.3061Condorelli R., Spring L., O’Shaughnessy J., et al. Polyclonal RB1 mutations and acquired resistance to CDK4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol 2018;29(3):640–645. https://doi.org/10.1093/annonc/mdx784Condorelli R., Spring L., O’Shaughnessy J., et al. Polyclonal RB1 mutations and acquired resistance to CDK4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol 2018;29(3):640–645. https://doi.org/10.1093/annonc/mdx784Dean J.L., Thangavel C., McClendon A.K., et al. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 2010;29(28):4018–4032. https://doi.org/10.1038/onc.2010.154Dean J.L., Thangavel C., McClendon A.K., et al. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 2010;29(28):4018–4032. https://doi.org/10.1038/onc.2010.154Malorni L., Piazza S., Ciani Y., et al. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget 2016;7(42):68012–68022. https://doi.org/10.18632/oncotarget.12010Malorni L., Piazza S., Ciani Y., et al. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget 2016;7(42):68012–68022. https://doi.org/10.18632/oncotarget.12010Xi J., Ma C.X. Sequencing endocrine therapy for metastatic breast cancer: what do we do after disease progression on a CDK4/6 inhibitor? Curr Oncol Rep 2020;22(6):57. https://doi.org/10.1007/s11912-020-00917-8Xi J., Ma C.X. Sequencing endocrine therapy for metastatic breast cancer: what do we do after disease progression on a CDK4/6 inhibitor? Curr Oncol Rep 2020;22(6):57. https://doi.org/10.1007/s11912-020-00917-8Ramanujan A., Tiwari S. APC/C and retinoblastoma interaction: cross-talk of retinoblastoma protein with the ubiquitin proteasome pathway. Biosci Rep 2016;36(5):e00377. https://doi.org/10.1042/BSR20160152Ramanujan A., Tiwari S. APC/C and retinoblastoma interaction: cross-talk of retinoblastoma protein with the ubiquitin proteasome pathway. Biosci Rep 2016;36(5):e00377. https://doi.org/10.1042/BSR20160152The I., Ruijtenberg S., Bouchet B.P. Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells. Nat Commun 2015;6:5906. https://doi.org/10.1038/ncomms6906The I., Ruijtenberg S., Bouchet B.P. Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells. Nat Commun 2015;6:5906. https://doi.org/10.1038/ncomms6906Serrano M., Hannon G.J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366(6456):704–707. https://doi.org/10.1038/366704a0Serrano M., Hannon G.J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366(6456):704–707. https://doi.org/10.1038/366704a0Dean J.L., McClendon A.K., Hickey T.E., et al Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 2012;11(14):2756–2761. https://doi.org/10.4161/cc.21195Dean J.L., McClendon A.K., Hickey T.E., et al Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 2012;11(14):2756–2761. https://doi.org/10.4161/cc.21195DeMichele A., Clark A.S., Tan K.S., et al. CDK4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015;21(5):995–1001. https://doi.org/10.1158/1078-0432.CCR-14-2258DeMichele A., Clark A.S., Tan K.S., et al. CDK4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015;21(5):995–1001. https://doi.org/10.1158/1078-0432.CCR-14-2258Witkiewicz A.K., Knudsen K.E., Dicker A.P., Knudsen E.S. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle 2011;10(15):2497–2503. https://doi.org/10.4161/cc.10.15.16776Witkiewicz A.K., Knudsen K.E., Dicker A.P., Knudsen E.S. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle 2011;10(15):2497–2503. https://doi.org/10.4161/cc.10.15.16776Miller T.W., Rexer B.N., Garrett J.T., Arteaga C.L. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 2011;13(6):224. https://doi.org/10.1186/bcr3039Miller T.W., Rexer B.N., Garrett J.T., Arteaga C.L. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 2011;13(6):224. https://doi.org/10.1186/bcr3039Dosil M.A., Mirantes C., Eritja N., et al. Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias. J Pathol 2017;242(2):152–164. https://doi.org/10.1002/path.4896Dosil M.A., Mirantes C., Eritja N., et al. Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias. J Pathol 2017;242(2):152–164. https://doi.org/10.1002/path.4896Costa C., Wang Y., Ly A., et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov 2020;10(1):72–85. https://doi.org/10.1158/2159-8290.CD-18-0830Costa C., Wang Y., Ly A., et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov 2020;10(1):72–85. https://doi.org/10.1158/2159-8290.CD-18-0830André F., Ciruelos E., Rubovszky G., et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019;380(20):1929–1940. https://doi.org/10.1056/NEJMoa1813904André F., Ciruelos E., Rubovszky G., et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019;380(20):1929–1940. https://doi.org/10.1056/NEJMoa1813904Razavi P., Chang M.T., Xu G., et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 2018;34(3):427–438.e6. https://doi.org/10.1016/j.ccell.2018.08.008Razavi P., Chang M.T., Xu G., et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 2018;34(3):427–438.e6. https://doi.org/10.1016/j.ccell.2018.08.008Brewer J.R., Mazot P., Soriano P. Genetic insights into the mechanisms of Fgf signaling. Genes Dev 2016;30(7):751–771. https://doi.org/10.1101/gad.277137.115Brewer J.R., Mazot P., Soriano P. Genetic insights into the mechanisms of Fgf signaling. Genes Dev 2016;30(7):751–771. https://doi.org/10.1101/gad.277137.115Guerrero-Zotano A., Mayer I.A., Arteaga C.L. PI3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev 2016;35(4):515–524. https://doi.org/10.1007/s10555-016-9637-xGuerrero-Zotano A., Mayer I.A., Arteaga C.L. PI3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev 2016;35(4):515–524. https://doi.org/10.1007/s10555-016-9637-xTurner N., Pearson A., Sharpe R., et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 2010;70(5):2085–2094. https://doi.org/10.1158/0008-5472.CAN-09-3746Turner N., Pearson A., Sharpe R., et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 2010;70(5):2085–2094. https://doi.org/10.1158/0008-5472.CAN-09-3746Formisano L., Stauffer K.M., Young C.D., et al. Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer. Clin Cancer Res 2017;23(20):6138– 6150. https://doi.org/10.1158/1078-0432.CCR-17-1232Formisano L., Stauffer K.M., Young C.D., et al. Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer. Clin Cancer Res 2017;23(20):6138– 6150. https://doi.org/10.1158/1078-0432.CCR-17-1232Mao P., Cohen O., Kowalski K.J., et al. Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer. Clin Cancer Res 2020;26(22):5974–5989. https://doi.org/10.1158/1078-0432.CCR-19-3958Mao P., Cohen O., Kowalski K.J., et al. Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer. Clin Cancer Res 2020;26(22):5974–5989. https://doi.org/10.1158/1078-0432.CCR-19-3958Shi P., Feng J., Chen C. Hippo pathway in mammary gland development and breast cancer. Acta Biochim Biophys Sin (Shanghai) 2015;47(1):53–59. https://doi.org/10.1093/abbs/gmu114Shi P., Feng J., Chen C. Hippo pathway in mammary gland development and breast cancer. Acta Biochim Biophys Sin (Shanghai) 2015;47(1):53–59. https://doi.org/10.1093/abbs/gmu114Gujral T.S., Kirschner M.W. Hippo pathway mediates resistance to cytotoxic drugs. Proc Natl Acad Sci U S A 2017;114(18):E3729–E3738. https://doi.org/10.1073/pnas.1703096114Gujral T.S., Kirschner M.W. Hippo pathway mediates resistance to cytotoxic drugs. Proc Natl Acad Sci U S A 2017;114(18):E3729–E3738. https://doi.org/10.1073/pnas.1703096114Li Z., Razavi P., Li Q., et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the hippo pathway. Cancer Cell 2018;34(6):893–905.e8. https://doi.org/10.1016/j.ccell.2018.11.006.Li Z., Razavi P., Li Q., et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the hippo pathway. Cancer Cell 2018;34(6):893–905.e8. https://doi.org/10.1016/j.ccell.2018.11.006.

The authors declare that there are no conflicts of interest present.