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  4. Vol 4, Issue 1, 2023

Targeting Cyclin Dependent Kinase 4/6 for Cancer Therapy

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DOI: 10.23977/tranc.2023.040105 | Downloads: 17 | Views: 520

Author(s)

Suxia Shi 1,2

Affiliation(s)

1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Chengdu, 610041, China
2 Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China

Corresponding Author

Suxia Shi

ABSTRACT

One fundamental hallmark of cancer is uncontrolled cell proliferation. In order to inhibit tumor growth, understanding the mechanisms of disease pathogenesis and the role of cell-cycle regulators which control the division process of cancer cells is necessary, specially CDK4/6, which have been approved as effective therapeutic targets in clinical studies. To date, five CDK4/6 inhibitors have been approved by the U.S. Food and Drug Administration (FDA) and National Medical Products Administration (NMPA). As expected, CDK4/6 inhibitors arrest tumor cells in the G1 phase of the cell cycle. Although undesired, mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge, and extending the use of CDK4/6 inhibitors beyond HR-positive breast cancer is still under consideration and practice. In this assay, we highlight the biological functions of CDK4/6 in the control of cell cycle progression in normal cells and summarize the multiple mechanisms by which the dysregulation of the CDK4/6 pathway of cancer cells. This review also provides a general overview of CDK4/6 inhibitors clinically approved. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results for cancer therapy. We also demonstrate the possible combination with available targeted therapies, immunotherapy, or classical chemotherapy to improve future therapeutic uses of CDK4/6 inhibition in a variety of cancers in clinical trials.

KEYWORDS

Cell cycle, CDK4/6 biology, CDK4/6 inhibitors, clinical trials, combination therapy

CITE THIS PAPER

Suxia Shi, Targeting Cyclin Dependent Kinase 4/6 for Cancer Therapy. Transactions on Cancer (2023) Vol. 4: 27-42. DOI: http://dx.doi.org/10.23977/tranc.2023.040105.

REFERENCES

[1] He, W., et al., Cancer Treatment Evolution from Traditional Methods to Stem Cells and Gene Therapy. Current Gene Therapy, 2022. 22(5): p. 368-385.
[2] Michaloglou, C., et al., Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor–positive Breast Cancer. Molecular Cancer Therapeutics, 2018. 17(5): p. 908-920.
[3] Coulonval, K., et al., Monoclonal antibodies to activated CDK4: use to investigate normal and cancerous cell cycle regulation and involvement of phosphorylations of p21 and p27. Cell Cycle, 2022. 21(1): p. 12-32.
[4] Sotillo, R., et al., Invasive melanoma in Cdk4-targeted mice. Proc Natl Acad Sci U S A, 2001. 98(23): p. 13312-7.
[5] Kumar, C.C., Signaling by integrin receptors. Oncogene, 1998. 17(11 Reviews): p. 1365-73.
[6] Wang, G., et al., Increased cyclin-dependent kinase 6 expression in bladder cancer. Oncol Lett, 2012. 4(1): p. 43-46.
[7] Whiteway, S.L., et al., Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells. J Neurooncol, 2013. 111(2): p. 113-21.
[8] Tsai, J.W., et al., Recurrent amplification at 7q21.2 Targets CDK6 gene in primary myxofibrosarcomas and identifies CDK6 overexpression as an independent adverse prognosticator. Ann Surg Oncol, 2012. 19(8): p. 2716-25.
[9] Ng, Y.L.D., et al., Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma. Nat Commun, 2022. 13(1): p. 1009.
[10] Yang, C., et al., Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene, 2017. 36(16): p. 2255-2264.
[11] Musgrove, E.A., et al., Cyclin D as a therapeutic target in cancer. Nat Rev Cancer, 2011. 11(8): p. 558-72.
[12] Beroukhim, R., et al., The landscape of somatic copy-number alteration across human cancers. Nature, 2010. 463(7283): p. 899-905.
[13] Choi, Y.J., et al., The requirement for cyclin D function in tumor maintenance. Cancer Cell, 2012. 22(4): p. 438-51.
[14] Filipits, M., et al., Cyclin D3 is a predictive and prognostic factor in diffuse large B-cel l lymphoma. Clinical cancer research: an official journal of the American Associa tion for Cancer Research, 2002. 8(3): p. 729-33.
[15] Flørenes, V.A., et al., Levels of cyclin D1 and D3 in malignant melanoma: deregulated cyclin D 3 expression is associated with poor clinical outcome in superficial m elanoma. Clinical cancer research: an official journal of the American Associa tion for Cancer Research, 2000. 6(9): p. 3614-20.
[16] Gong, X., 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): p. 761-776 e6.
[17] Xue, Y., et al., SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat Commun, 2019. 10(1): p. 557.
[18] Condorelli, R., et al., Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol, 2018. 29(3): p. 640-645.
[19] Rubio, C., et al., CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status. Clin Cancer Res, 2019. 25(1): p. 390-402.
[20] Rivadeneira, D.B., et al., Proliferative Suppression by CDK4/6 Inhibition: Complex Function of the Retinoblastoma Pathway in Liver Tissue and Hepatoma Cells. Gastroenterology, 2010. 138(5): p. 1920-1930.e2.
[21] Guerrero-Zotano, A.L., et al., ER(+) Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors. Clin Cancer Res, 2018. 24(11): p. 2517-2529.
[22] Ma, Y., et al., A small-molecule E2F inhibitor blocks growth in a melanoma culture model. Cancer Res, 2008. 68(15): p. 6292-9.
[23] Lan, W., et al., E2F signature is predictive for the pancreatic adenocarcinoma clinical outcome and sensitivity to E2F inhibitors, but not for the response to cytotoxic-based treatments. Sci Rep, 2018. 8(1): p. 8330.
[24] Chen, S.H., et al., RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1. Oncogene, 2018. 37(6): p. 821-832.
[25] Finn, R.S., et al., PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res, 2009. 11(5): p. R77.
[26] Qin, G., et al., Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway. Oncotarget, 2015. 6(39): p. 41794-808.
[27] Finn, R.S., et al., The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol, 2015. 16(1): p. 25-35.
[28] Finn, R.S., et al., Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med, 2016. 375(20): p. 1925-1936.
[29] Rugo, H.S., et al., 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. 174(3): p. 719-729.
[30] Turner, N.C., et al., Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med, 2018. 379(20): p. 1926-1936.
[31] Cristofanilli, M., et al., Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol, 2016. 17(4): p. 425-439.
[32] Hortobagyi, G.N., et al., Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med, 2016. 375(18): p. 1738-1748. 
[33] Slamon, D.J., et al., Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol, 2018. 36(24): p. 2465-2472.
[34] Slamon, D.J., et al., Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med, 2020. 382(6): p. 514-524.
[35] Slamon, D.J., et al., Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol, 2021. 32(8): p. 1015-1024.
[36] Harbeck, N., et al., Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol, 2020. 12: p. 1758835920943065.
[37] Dickler, M.N., et al., MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR(+)/HER2(-) Metastatic Breast Cancer. Clin Cancer Res, 2017. 23(17): p. 5218-5224.
[38] Sledge, G.W., Jr., et al., MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol, 2017. 35(25): p. 2875-2884.
[39] Sledge, G.W., Jr., et al., The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol, 2020. 6(1): p. 116-124.
[40] Goetz, M.P., et al., MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol, 2017. 35(32): p. 3638-3646.
[41] Johnston, S., et al., MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer, 2019. 5: p. 5.
[42] Raub, T.J., et al., Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft. Drug Metab Dispos, 2015. 43(9): p. 1360-71.
[43] Schaer, D.A., et al., The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade. Cell Rep, 2018. 22(11): p. 2978-2994.
[44] Tolaney, S.M., et al., Updated efficacy, safety, & PD-L1 status of patients with HR+, HER2- metastatic breast cancer administered abemaciclib plus pembrolizumab. Journal of Clinical Oncology, 2018. 36: p. 1059-1059.
[45] Long, F., 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): p. 1420-1430.
[46] Zhang, P., et al., A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer. Biomark Res, 2021. 9(1): p. 24.
[47] Xu, B., 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): p. 1904-1909.
[48] Weiss, J., et al., Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies. Clin Lung Cancer, 2021. 22(5): p. 449-460.
[49] Hart, L.L., et al., Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study. Adv Ther, 2021. 38(1): p. 350-365.
[50] Dean, J.L., A.K. McClendon, and E.S. Knudsen, Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem, 2012. 287(34): p. 29075-87.
[51] McClendon, A.K., et al., CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle, 2012. 11(14): p. 2747-55.
[52] Gao, Y., et al., Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosiss. Cell Oncol (Dordr), 2017. 40(3): p. 209-218.
[53] Roberts, P.J., et al., Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows. Mol Cancer Ther, 2020. 19(8): p. 1575-1588.
[54] Bosacki, C., et al., CDK 4/6 inhibitors combined with radiotherapy: A review of literature. Clin Transl Radiat Oncol, 2021. 26: p. 79-85.
[55] Horsley, V., et al., NFATc1 balances quiescence and proliferation of skin stem cells. Cell, 2008. 132(2): p. 299-310.
[56] Hagen, K.R., et al., Silencing CDK4 radiosensitizes breast cancer cells by promoting apoptosis. Cell Div, 2013. 8(1): p. 10.
[57] Han, Y.K., et al., A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy. Biochem Biophys Res Commun, 2013. 430(4): p. 1329-33.
[58] Petroni, G., et al., Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER(+) Breast Cancer. Clin Cancer Res, 2021. 27(7): p. 1855-1863.
[59] Hashizume, R., et al., Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. Neuro Oncol, 2016. 18(11): p. 1519-1528.
[60] Knudsen, E.S., et al., Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene, 2019. 38(18): p. 3355-3370.
[61] Divakar, S.K., et al., Dual inhibition of CDK4/Rb and PI3K/AKT/mTOR pathways by ON123300 induces synthetic lethality in mantle cell lymphomas. Leukemia, 2016. 30(1): p. 86-93.
[62] Goel, S., et al., CDK4/6 inhibition triggers anti-tumour immunity. (1476-4687 (Electronic)).
[63] Zhang, J., et al., Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature, 2018. 553(7686): p. 91-95.
[64] Uzhachenko, R.V., et al., Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors. Cell Rep, 2021. 35(1): p. 108944.
[65] Brand, M., et al., Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML. Cell Chem Biol, 2019. 26(2): p. 300-306 e9.

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