Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity
The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed th...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/12/6547 |
| _version_ | 1797486557105487872 |
|---|---|
| author | Nischal Koirala Nandini Dey Jennifer Aske Pradip De |
| author_facet | Nischal Koirala Nandini Dey Jennifer Aske Pradip De |
| author_sort | Nischal Koirala |
| collection | DOAJ |
| description | The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed therapies and develop a more aggressive disease phenotype. One of these mechanisms is the crosstalk between ER and HER2 signaling, especially the CDK4/6-Cyclin D-Rb signaling axis that is commonly active and has received attention for its potential role in regulating tumor progression. CDK 4/6 inhibitors interfere with the binding of cell-cycle-dependent kinases (CDKs) with their cognate partner cyclins, and forestall the progression of the cell cycle by preventing Rb phosphorylation and E2F release that consequentially leads to cancer cell senescence. CDK 4/6 inhibitors, namely, palbociclib, ribociclib, and abemaciclib, in combination with anti-estrogen therapies, have shown impressive outcomes in hormonal receptor-positive (HR+) disease and have received approval for this disease context. As an extension of this concept, preclinical/clinical studies incorporating CDK 4/6 inhibitors with HER2-targeted drugs have been evaluated and have shown potency in limiting tumor progression, restoring therapeutic sensitivity, and may improving the management of the disease. Currently, several clinical trials are examining the synergistic effects of CDK 4/6 inhibitors with optimized HER2-directed therapies for the (ER+/-) HER2+ population in the metastatic setting. In this review, we aim to interrogate the burden of HER2+ disease in light of recent treatment progress in the field and examine the clinical benefit of CDK 4/6 inhibitors as a replacement for traditional chemotherapy to improve outcomes in HER2+ breast cancer. |
| first_indexed | 2024-03-09T23:34:55Z |
| format | Article |
| id | doaj.art-38c0d7ad582f4e30878d3ac920b921c6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:34:55Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-38c0d7ad582f4e30878d3ac920b921c62023-11-23T17:02:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312654710.3390/ijms23126547Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment OpportunityNischal Koirala0Nandini Dey1Jennifer Aske2Pradip De3Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USATranslational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USATranslational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USATranslational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USAThe development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed therapies and develop a more aggressive disease phenotype. One of these mechanisms is the crosstalk between ER and HER2 signaling, especially the CDK4/6-Cyclin D-Rb signaling axis that is commonly active and has received attention for its potential role in regulating tumor progression. CDK 4/6 inhibitors interfere with the binding of cell-cycle-dependent kinases (CDKs) with their cognate partner cyclins, and forestall the progression of the cell cycle by preventing Rb phosphorylation and E2F release that consequentially leads to cancer cell senescence. CDK 4/6 inhibitors, namely, palbociclib, ribociclib, and abemaciclib, in combination with anti-estrogen therapies, have shown impressive outcomes in hormonal receptor-positive (HR+) disease and have received approval for this disease context. As an extension of this concept, preclinical/clinical studies incorporating CDK 4/6 inhibitors with HER2-targeted drugs have been evaluated and have shown potency in limiting tumor progression, restoring therapeutic sensitivity, and may improving the management of the disease. Currently, several clinical trials are examining the synergistic effects of CDK 4/6 inhibitors with optimized HER2-directed therapies for the (ER+/-) HER2+ population in the metastatic setting. In this review, we aim to interrogate the burden of HER2+ disease in light of recent treatment progress in the field and examine the clinical benefit of CDK 4/6 inhibitors as a replacement for traditional chemotherapy to improve outcomes in HER2+ breast cancer.https://www.mdpi.com/1422-0067/23/12/6547brain metastasiscell cycle inhibitorscell cycle pathwayERBB2HER2+ breast cancerHER2-targeted drug delivery |
| spellingShingle | Nischal Koirala Nandini Dey Jennifer Aske Pradip De Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity International Journal of Molecular Sciences brain metastasis cell cycle inhibitors cell cycle pathway ERBB2 HER2+ breast cancer HER2-targeted drug delivery |
| title | Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity |
| title_full | Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity |
| title_fullStr | Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity |
| title_full_unstemmed | Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity |
| title_short | Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity |
| title_sort | targeting cell cycle progression in her2 breast cancer an emerging treatment opportunity |
| topic | brain metastasis cell cycle inhibitors cell cycle pathway ERBB2 HER2+ breast cancer HER2-targeted drug delivery |
| url | https://www.mdpi.com/1422-0067/23/12/6547 |
| work_keys_str_mv | AT nischalkoirala targetingcellcycleprogressioninher2breastcanceranemergingtreatmentopportunity AT nandinidey targetingcellcycleprogressioninher2breastcanceranemergingtreatmentopportunity AT jenniferaske targetingcellcycleprogressioninher2breastcanceranemergingtreatmentopportunity AT pradipde targetingcellcycleprogressioninher2breastcanceranemergingtreatmentopportunity |