Targeting CDK2 to Combat Drug Resistance in Cancer Therapy

Overview

Journal Future Oncol

Specialty Oncology

Date 2024 Oct 29

PMID 39469865

Authors

Sara Kasirzadeh

Jimma Likisa Lenjisa

Shudong Wang

Affiliations

Soon will be listed here.

Abstract

Drug resistance remains a major obstacle in cancer treatment, leading to treatment failures and high mortality rates. Despite advancements in therapies, overcoming resistance requires a deeper understanding of its mechanisms. This review highlights CDK2's pivotal role in both intrinsic and acquired resistance, and its potential as a therapeutic target. Cyclin E upregulation, which partners with CDK2, is linked to poor prognosis and resistance across various cancers. Specifically, amplifications of are associated with resistance to targeted therapies, immunotherapy, endocrine therapies and chemo/radiotherapy. Given CDK2's involvement in resistance mechanisms, investigating its role presents promising opportunities for developing novel strategies to combat resistance and improve treatment outcomes.

Citing Articles

Novel Bicyclic Amines as CDK2 Inhibitors for Treating Metastatic Breast Cancer or Metastatic Lung Cancer.

Sabnis R ACS Med Chem Lett. 2025; 16(2):198-199.

PMID: 39967632 PMC: 11831556. DOI: 10.1021/acsmedchemlett.5c00005.

References

Caruso J, Duong M, Carey J, Hunt K, Keyomarsi K . Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies. Cancer Res. 2018; 78(19):5481-5491. PMC: 6168358. DOI: 10.1158/0008-5472.CAN-18-1235. View

Al-Qasem A, Alves C, Ehmsen S, Tuttolomondo M, Terp M, Johansen L . Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer. NPJ Precis Oncol. 2022; 6(1):68. PMC: 9509389. DOI: 10.1038/s41698-022-00311-6. View

Scaltriti M, Eichhorn P, Cortes J, Prudkin L, Aura C, Jimenez J . Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci U S A. 2011; 108(9):3761-6. PMC: 3048107. DOI: 10.1073/pnas.1014835108. View

Nair B, Vallabhaneni S, Tekmal R, Vadlamudi R . Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells. Breast Cancer Res. 2011; 13(3):R80. PMC: 3218960. DOI: 10.1186/bcr2929. View

Asghar U, Kanani R, Roylance R, Mittnacht S . Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer. JCO Precis Oncol. 2022; 6:e2100002. PMC: 8769124. DOI: 10.1200/PO.21.00002. View

Schaefer I, Hemming M, Lundberg M, Serrata M, Goldaracena I, Liu N . Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST. Br J Cancer. 2022; 127(11):2072-2085. PMC: 9681737. DOI: 10.1038/s41416-022-01990-5. View

Poon E, Liang T, Jamin Y, Walz S, Kwok C, Hakkert A . Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma. J Clin Invest. 2020; 130(11):5875-5892. PMC: 7598076. DOI: 10.1172/JCI134132. View

Gorski J, Ueland F, Kolesar J . CCNE1 Amplification as a Predictive Biomarker of Chemotherapy Resistance in Epithelial Ovarian Cancer. Diagnostics (Basel). 2020; 10(5). PMC: 7277958. DOI: 10.3390/diagnostics10050279. View

Doostan I, Karakas C, Kohansal M, Low K, Ellis M, Olson Jr J . Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer. Clin Cancer Res. 2017; 23(23):7288-7300. PMC: 5768442. DOI: 10.1158/1078-0432.CCR-17-1544. View

10.

Cusan M, Mungo G, De Marco Zompit M, Segatto I, Belletti B, Baldassarre G . Landscape of CDKN1B Mutations in Luminal Breast Cancer and Other Hormone-Driven Human Tumors. Front Endocrinol (Lausanne). 2018; 9:393. PMC: 6056726. DOI: 10.3389/fendo.2018.00393. View

11.

Dietrich C, Trub A, Ahn A, Taylor M, Ambani K, Chan K . INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors. Cancer Discov. 2023; 14(3):446-467. PMC: 10905675. DOI: 10.1158/2159-8290.CD-23-0954. View

12.

Balakrishnan K, Chen Y, Dong J . Amplified Cell Cycle Genes Identified in High-Grade Serous Ovarian Cancer. Cancers (Basel). 2024; 16(16). PMC: 11352846. DOI: 10.3390/cancers16162783. View

13.

Wang J, Yang T, Xu G, Liu H, Ren C, Xie W . Cyclin-Dependent Kinase 2 Promotes Tumor Proliferation and Induces Radio Resistance in Glioblastoma. Transl Oncol. 2016; 9(6):548-556. PMC: 5118617. DOI: 10.1016/j.tranon.2016.08.007. View

14.

Cocco E, Lopez S, Black J, Bellone S, Bonazzoli E, Predolini F . Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo. Br J Cancer. 2016; 115(3):303-11. PMC: 4973158. DOI: 10.1038/bjc.2016.198. View

15.

Stone A, Sutherland R, Musgrove E . Inhibitors of cell cycle kinases: recent advances and future prospects as cancer therapeutics. Crit Rev Oncog. 2012; 17(2):175-98. DOI: 10.1615/critrevoncog.v17.i2.40. View

16.

Roninson I . Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. Cancer Lett. 2002; 179(1):1-14. DOI: 10.1016/s0304-3835(01)00847-3. View

17.

Patch A, Christie E, Etemadmoghadam D, Garsed D, George J, Fereday S . Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015; 521(7553):489-94. DOI: 10.1038/nature14410. View

18.

Decker J, Kandagatla P, Wan L, Bernstein R, Ma J, Shea L . Cyclin E overexpression confers resistance to trastuzumab through noncanonical phosphorylation of SMAD3 in HER2+ breast cancer. Cancer Biol Ther. 2020; 21(11):994-1004. PMC: 7678934. DOI: 10.1080/15384047.2020.1818518. View

19.

Wang Y, Pattarayan D, Huang H, Zhao Y, Li S, Wang Y . Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer. Nat Commun. 2024; 15(1):3178. PMC: 11015024. DOI: 10.1038/s41467-024-47433-y. View

20.

Brown V, Moore S, Chen M, House N, Ramsden P, Wu H . CDK2 regulates collapsed replication fork repair in CCNE1-amplified ovarian cancer cells via homologous recombination. NAR Cancer. 2023; 5(3):zcad039. PMC: 10373114. DOI: 10.1093/narcan/zcad039. View