Immunomodulation by Anticancer Cell Cycle Inhibitors

Overview

Journal Nat Rev Immunol

Specialty Allergy & Immunology

Date 2020 Apr 30

PMID 32346095

Citations 63

Authors

Giulia Petroni

Silvia C Formenti

Selina Chen-Kiang

Lorenzo Galluzzi

Affiliations

Soon will be listed here.

Abstract

Cell cycle proteins that are often dysregulated in malignant cells, such as cyclin-dependent kinase 4 (CDK4) and CDK6, have attracted considerable interest as potential targets for cancer therapy. In this context, multiple inhibitors of CDK4 and CDK6 have been developed, including three small molecules (palbociclib, abemaciclib and ribociclib) that are currently approved for the treatment of patients with breast cancer and are being extensively tested in individuals with other solid and haematological malignancies. Accumulating preclinical and clinical evidence indicates that the anticancer activity of CDK4/CDK6 inhibitors results not only from their ability to block the cell cycle in malignant cells but also from a range of immunostimulatory effects. In this Review, we discuss the ability of anticancer cell cycle inhibitors to modulate various immune functions in support of effective antitumour immunity.

Citing Articles

Double-Faced Immunological Effects of CDK4/6 Inhibitors on Cancer Treatment: Challenges and Perspectives.

Liu Y, Deng Y, Yang C, Naranmandura H Bioengineering (Basel). 2024; 11(11).

PMID: 39593745 PMC: 11591775. DOI: 10.3390/bioengineering11111084.

Palbociclib and letrozole for hormone receptor-positive HER2-negative breast cancer with residual disease after neoadjuvant chemotherapy.

Pernas S, Sanfeliu E, Villacampa G, Salvador J, Perello A, Gonzalez X NPJ Breast Cancer. 2024; 10(1):101.

PMID: 39592624 PMC: 11599376. DOI: 10.1038/s41523-024-00710-x.

Cell cycle inhibitors activate the hypoxia-induced DDX41/STING pathway to mediate antitumor immune response in liver cancer.

Wong P, Chan C, Xue H, Goh C, Cheu J, Tse A JCI Insight. 2024; 9(22).

PMID: 39388278 PMC: 11601891. DOI: 10.1172/jci.insight.170532.

Identification of CDK4/6 Inhibitors as Small Molecule NLRP3 Inflammasome Activators that Facilitate IL-1β Secretion and T Cell Adjuvanticity.

Weiss A, Lopez 2nd M, Rosenberger M, Kim J, Shen J, Chen Q J Med Chem. 2024; 67(17):14974-14985.

PMID: 39162654 PMC: 11736968. DOI: 10.1021/acs.jmedchem.4c00516.

Strategies to enhance the therapeutic efficacy of anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody in cancer therapy.

Su X, Li J, Xu X, Ye Y, Wang C, Pang G J Transl Med. 2024; 22(1):751.

PMID: 39123227 PMC: 11316358. DOI: 10.1186/s12967-024-05552-6.

References

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

Woods D, Turchi J . Chemotherapy induced DNA damage response: convergence of drugs and pathways. Cancer Biol Ther. 2013; 14(5):379-89. PMC: 3672181. DOI: 10.4161/cbt.23761. View

Schirrmacher V . From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review). Int J Oncol. 2018; 54(2):407-419. PMC: 6317661. DOI: 10.3892/ijo.2018.4661. View

Kent L, Leone G . The broken cycle: E2F dysfunction in cancer. Nat Rev Cancer. 2019; 19(6):326-338. DOI: 10.1038/s41568-019-0143-7. View

Fry D, Harvey P, Keller P, Elliott W, Meade M, Trachet E . Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004; 3(11):1427-38. View

OLeary B, Finn R, Turner N . Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016; 13(7):417-30. DOI: 10.1038/nrclinonc.2016.26. View

Baughn L, Di Liberto M, Wu K, Toogood P, Louie T, Gottschalk R . A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res. 2006; 66(15):7661-7. DOI: 10.1158/0008-5472.CAN-06-1098. View

Leonard J, LaCasce A, Smith M, Noy A, Chirieac L, Rodig S . Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012; 119(20):4597-607. DOI: 10.1182/blood-2011-10-388298. View

Harbour J, Luo R, Dei Santi A, Postigo A, Dean D . Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999; 98(6):859-69. DOI: 10.1016/s0092-8674(00)81519-6. View

10.

Condorelli R, Spring L, OShaughnessy J, Lacroix L, Bailleux C, Scott V . Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol. 2017; 29(3):640-645. DOI: 10.1093/annonc/mdx784. View

11.

OLeary B, Cutts R, Liu Y, Hrebien S, Huang X, Fenwick K . The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov. 2018; 8(11):1390-1403. PMC: 6368247. DOI: 10.1158/2159-8290.CD-18-0264. View

12.

Niu Y, Xu J, Sun T . Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies. J Cancer. 2019; 10(22):5504-5517. PMC: 6775706. DOI: 10.7150/jca.32628. View

13.

Klein M, Kovatcheva M, Davis L, Tap W, Koff A . CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought. Cancer Cell. 2018; 34(1):9-20. PMC: 6039233. DOI: 10.1016/j.ccell.2018.03.023. View

14.

Wang H, Nicolay B, Chick J, Gao X, Geng Y, Ren H . The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature. 2017; 546(7658):426-430. PMC: 5516959. DOI: 10.1038/nature22797. View

15.

Lopez-Mejia I, Lagarrigue S, Giralt A, Martinez-Carreres L, Zanou N, Denechaud P . CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation. Mol Cell. 2017; 68(2):336-349.e6. DOI: 10.1016/j.molcel.2017.09.034. View

16.

Martinez-Carreres L, Puyal J, Leal-Esteban L, Orpinell M, Castillo-Armengol J, Giralt A . CDK4 Regulates Lysosomal Function and mTORC1 Activation to Promote Cancer Cell Survival. Cancer Res. 2019; 79(20):5245-5259. PMC: 7611450. DOI: 10.1158/0008-5472.CAN-19-0708. View

17.

Liu T, Yu J, Deng M, Yin Y, Zhang H, Luo K . CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. Nat Commun. 2017; 8:13923. PMC: 5228031. DOI: 10.1038/ncomms13923. View

18.

Ameratunga M, Kipps E, Okines A, Lopez J . To Cycle or Fight-CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity. Clin Cancer Res. 2018; 25(1):21-28. DOI: 10.1158/1078-0432.CCR-18-1999. View

19.

Laphanuwat P, Jirawatnotai S . Immunomodulatory Roles of Cell Cycle Regulators. Front Cell Dev Biol. 2019; 7:23. PMC: 6399147. DOI: 10.3389/fcell.2019.00023. View

20.

Rane S, Dubus P, Mettus R, Galbreath E, Boden G, Reddy E . Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet. 1999; 22(1):44-52. DOI: 10.1038/8751. View