Fol. Biol. 2026, 72, 59-67
https://doi.org/10.14712/fb2026.0006
Wip1 Inhibition Enhances the Therapeutic Efficacy of Palbociclib in Luminal A Breast Cancer by Modulating Cell Cycle Progression and Apoptosis
Gökhan Çolak1
, Nazllcan Kaygusuz2,3, Nezih Meydan1,4, Esin Oktay1, Mehtap Kılıc Eren2,5
, Nazllcan Kaygusuz2,3, Nezih Meydan1,4, Esin Oktay1, Mehtap Kılıc Eren2,5
1Faculty of Medicine, Department of Medical Oncology, Aydin Adnan Menderes University, Aydin, Türkiye
2Faculty of Medicine, Department of Medical Biology, Aydin Adnan Menderes University, Aydin, Türkiye
3Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir, Türkiye
4Department of Medical Oncology, Medicana International Hospital University, Istanbul, Türkiye
5ADU-BILTEM, Aydin Adnan Menderes University, Aydin, Türkiye
Received August 3, 2025
Accepted January 29, 2026
References
1. , M., Singh, R., Anwer, M. et al. (2022) The renaissance of CDK inhibitors in breast cancer therapy: an update on clinical trials and therapy resistance. Cancers (Basel) 14, 5388.
<https://doi.org/10.3390/cancers14215388>
2. , G. D., Prajapati, D. N., Mathure, D. et al. (2025) Advances in breast cancer therapy: “Exploring the therapeutic potential of CDK 4/6 inhibitors and their clinical impact.” Curr. Probl. Cancer 58, 101235.
<https://doi.org/10.1016/j.currproblcancer.2025.101235>
3. , S. G. (2023) The pathophysiology of the cell cycle in cancer and treatment strategies using various cell cycle checkpoint inhibitors. Pathol. Res. Pract. 251, 154854.
<https://doi.org/10.1016/j.prp.2023.154854>
4. , F., Laversanne, M., Sung, H. et al. (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA cancer J. Clin. 74, 229-263.
5. , B., Wabl, C. A., Gumusay, O. (2022) CDK4/6 inhibitors: mechanisms of resistance and potential biomarkers of responsiveness in breast cancer. Future Oncol. 18, 1143-1157.
<https://doi.org/10.2217/fon-2021-0842>
6. , R., Vishnubalaji, R., Manikandan, M. et al. (2019) Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo. Sci. Rep. 9, 13696.
<https://doi.org/10.1038/s41598-019-50140-0>
7. , A., Bulavin, D V. (2015) Wip1 phosphatase in breast cancer. Oncogene 34, 4429-4438.
<https://doi.org/10.1038/onc.2014.375>
8. , R. S., Dering, J., Conklin, D. et al. (2009) 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. 11, R77.
<https://doi.org/10.1186/bcr2419>
9. , A. K., Monteiro, A. N. (2010) Phosphatases in the cellular response to DNA damage. Cell Commun. Signal. 8, 27.
<https://doi.org/10.1186/1478-811X-8-27>
10. , R. J., Park, J., Asprer, K. J. et al. (2023) Updated review article: cyclin-dependent kinase 4/6 inhibitor impact, FDA approval, and resistance pathways. J. Pharm. Technol. 39, 298-308.
<https://doi.org/10.1177/87551225231205153>
11. , A., Faitg, T., Richter, M. et al. (2014) Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nat. Chem. Biol. 10, 181-187.
<https://doi.org/10.1038/nchembio.1427>
12. , M., Sotiriou, C. (2013) Luminal breast cancer: from biology to treatment. Nat. Rev. Clin. Oncol. 10, 494-506.
<https://doi.org/10.1038/nrclinonc.2013.124>
13. , W., Shi, Y., Wang, X. et al. (2019) Combined androgen receptor blockade overcomes the resistance of breast cancer cells to palbociclib. Int. J. Biol. Sci. 15, 522-532.
<https://doi.org/10.7150/ijbs.30572>
14. , E., Ogata, R., Saitoh, W. et al. (2020) Anti-cell growth and anti-cancer stem cell activity of the CDK4/6 inhibitor palbociclib in breast cancer cells. Breast Cancer 27, 415-425.
<https://doi.org/10.1007/s12282-019-01035-5>
15. , W., Jiang, X., Mercer, W. E. (2009) Downregulation of Wip-1 phosphatase expression in MCF-7 breast cancer cells enhances doxorubicin-induced apoptosis through p53-mediated transcriptional activation of Bax. Cancer Biol. Ther. 8, 555-563.
<https://doi.org/10.4161/cbt.8.6.7742>
16. , H. K., Bertoli, C., de Bruin R. A. M. (2022) Cell cycle control in cancer. Nat. Rev. Mol. Cell Biol. 23, 74-88.
<https://doi.org/10.1038/s41580-021-00404-3>
17. , R., Castellino, R. C. (2021) Phosphatase magnesium-dependent 1 δ (PPM1D), serine/threonine protein phosphatase and novel pharmacological target in cancer. Biochem. Pharmacol. 184, 114362.
<https://doi.org/10.1016/j.bcp.2020.114362>
18. , S., Kiyota, Y., Chuman, Y. et al. (2015) Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation. Bioorg. Med. Chem. 23, 6246-6249.
<https://doi.org/10.1016/j.bmc.2015.08.042>
19. , S., Burdová, K., Benada, J. et al. (2016) Inhibition of WIP1 phosphatase sensitizes breast cancer cells to genotoxic stress and to MDM2 antagonist nutlin-3. Oncotarget 7, 14458-14475.
<https://doi.org/10.18632/oncotarget.7363>
20. , H., Kilic-Eren, M. (2021) Targeting oncogenic WIP1 phosphatase sensitizes hypoxic breast cancer cells to doxorubicin induced apoptosis via activation of p53-p21 axis. Gene Rep. 23, 101144.
<https://doi.org/10.1016/j.genrep.2021.101144>
21. , N., Milioli, H. H., Alexandrou, S. et al. (2020) MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer. Breast Cancer Res. 22, 87.
<https://doi.org/10.1186/s13058-020-01318-2>
22. , H., Elango, R., Alajez, N. M. (2021) Molecular classification of breast cancer utilizing long non-coding RNA (lncRNA) transcriptomes identifies novel diagnostic lncRNA panel for triple-negative breast cancer. Cancers (Basel) 13, 5350.
<https://doi.org/10.3390/cancers13215350>
23. , S., Mehraj, U., Qayoom, H. et al. (2022) Cyclin-dependent kinases in breast cancer: expression pattern and therapeutic implications. Med. Oncol. 39, 106.
<https://doi.org/10.1007/s12032-022-01731-x>
24. , R, Calsina, B., Hermoso, A. et al. (2017) Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget 8, 69493-69507.
<https://doi.org/10.18632/oncotarget.17778>
25. , J. R., Vaillant, F., Surgenor, E. et al. (2020) Dual targeting of CDK4/6 and BCL2 pathways augments tumor response in estrogen receptor–positive breast cancer. Clin. Cancer Res. 26, 4120-4134.
<https://doi.org/10.1158/1078-0432.CCR-19-1872>
26. Wild, C. P., Weiderpass, E., Stewart, B. W. (Eds.) (2020) World Cancer Report: Cancer research for cancer prevention. International Agency for Research on Cancer, Lyon.
