Механизмы регуляции клеточного цикла CDK4 / 6 и пути формирования устойчивости к их ингибиторам (литературный обзор)

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 / C^MR1 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.

1. Breast cancer. World Health Organization (WHO). Available at: https://www.who.int/news-room/fact-sheets/detail/breast-cancer

2. Female Breast Cancer Subtypes. SEER Cancer Stat Facts. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html

3. Sotiriou C., Pusztai L. Gene-Expression Signatures in Breast Cancer. N Engl J Med 2009;360(8):790–800. https://doi.org/10.1056/NEJMra0801289

4. Ignatiadis 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.2013.123

5. Choi 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.2012.09.015

6. Filmus J., Robles A.I., Shi W., et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 1994;9(12):3627–3633

7. Ribnikar 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.2018.10.001

8. Konecny 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-10-2307

9. Herrera-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-15-0728

10. Malumbres M., Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009;9(3):153–166. https://doi.org/10.1038/nrc2602

11. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

12. Nurse P. Regulation of the eukaryotic cell cycle. Eur J Cancer 1997;33(7):1002–1004. https://doi.org/10.1016/S0959-8049(97)00067-2

13. Besson 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.2008.01.013

14. Lee 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.20.2.672-683.2000

15. Hatakeyama 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_2

16. Bertoli 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/nrm3629

17. Medema 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.92.14.6289

18. Nakayama 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-D

19. Yu Q., Geng Y., Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature. 2001;411(6841):1017– 1021. https://doi.org/10.1038/35082500

20. Yu 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.2005.12.012

21. Zwijsen 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)81879-6

22. Wu 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/10.1177/17588359241282499

23. Al-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.e20224

24. Prall 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)00021-1

25. Renoir 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.2012.10.018

26. Muise-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.273.45.29864

27. Viedma-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.2014.3190

28. Koirala 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/ijms23126547

29. Hu 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.S310649

30. Bosco 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.6.6.3988

31. Gelbert 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/s10637-014-0120-7

32. Wagner V., Gil J. Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene 2020;39(29):5165– 5176. https://doi.org/10.1038/s41388-020-1354-9

33. Anders 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.2011.10.001

34. Acevedo 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-15-2347

35. Torres-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.17778

36. Litchfield 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.27539

37. Hafner 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.2019.05.005

38. Portman 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/s10549-018-4901-0

39. Guiley 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.aaw2106

40. Pack 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-z

41. Guan 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/gkaa858

42. Watt 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-y

43. Whittle 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-19-1872

44. Brown 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-11-4139

45. Vijayaraghavan 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/ncomms15916

46. Yang 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.2016.379

47. Kollmann 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.2013.07.012

48. Yang 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-x

49. Patel 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.01206-14

50. Sutherland 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)90177-3

51. Foster 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.21.3.794-810.2001

52. Du 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.0104261

53. Gong 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.2017.11.006

54. Fribbens 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.2016.67.3061

55. Condorelli 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/mdx784

56. Dean 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.2010.154

57. Malorni 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.12010

58. Xi 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/s11912-020-00917-8

59. Ramanujan 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/BSR20160152

60. The 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/ncomms6906

61. Serrano 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/10.1038/366704a0

62. Dean 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.21195

63. DeMichele 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-14-2258

64. Witkiewicz 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.10.15.16776

65. Miller 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/bcr3039

66. Dosil 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.4896

67. Costa 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-18-0830

68. André 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/NEJMoa1813904

69. Razavi 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.2018.08.008

70. Brewer 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.277137.115

71. Guerrero-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-x

72. Turner 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-09-3746

73. Formisano 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-17-1232

74. Mao 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-19-3958

75. Shi 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/gmu114

76. Gujral 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.1703096114

77. 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.