The emerging role of CDK4/6i in HER2-positive breast cancer
Ciara C O'Sullivan1, Vera J Suman2, Matthew P Goetz3
1Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905-0002, USA.
Abstract:
Prior to the advent of the monoclonal antibody trastuzumab, human epidermal growth-factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) was associated with an aggressive clinical course and poor survival outcomes. In the era of effective HER2-directed therapies, median survival rates for patients with metastatic HER2+ BC now approach 5 years. Despite these improvements, the majority of affected patients unfortunately die from disease. Therapies to overcome treatment resistance are being actively pursued. One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6), as they are downstream of HER2 and many of the cellular pathways driving resistance to HER2-targeted therapies, and play a key role in proliferation by controlling transition through the G1 restriction point to the S phase of the cell cycle. In this article, we review the published literature with regard to the rationale for CDK4/6-directed therapies in HER2+ BC and discuss ongoing clinical research and new challenges in the field.
Insights
Targeting cyclin-dependent kinases 4/6 (CDK4/6) offers a promising strategy to overcome treatment resistance in human epidermal growth-factor receptor 2 (HER2)-positive breast cancer. This approach addresses key proliferation pathways driving disease progression.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Human epidermal growth-factor receptor 2 (HER2)-positive breast cancer (BC) historically had poor outcomes.
- Trastuzumab and other HER2-targeted therapies have improved survival but resistance remains a challenge.
- Cyclin-dependent kinases 4/6 (CDK4/6) are critical for cell cycle progression and implicated in resistance pathways.
Purpose of the Study:
- To review the rationale for targeting CDK4/6 in HER2-positive BC.
- To discuss the role of CDK4/6 in HER2-targeted therapy resistance.
- To summarize ongoing clinical research and challenges in this therapeutic area.
Main Methods:
- Literature review of published studies.
- Analysis of cellular pathways downstream of HER2.
- Examination of the role of CDK4/6 in cell cycle regulation.
Main Results:
- CDK4/6 inhibitors target a key mechanism of proliferation.
- CDK4/6 are downstream of HER2 and involved in resistance pathways.
- Clinical trials are investigating CDK4/6 inhibitors in combination with HER2-targeted therapies.
Conclusions:
- Targeting CDK4/6 is a rational strategy to overcome resistance in HER2+ BC.
- Further research and clinical trials are needed to optimize CDK4/6-directed therapies.
- Addressing CDK4/6 pathways may improve outcomes for patients with metastatic HER2+ BC.
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