Mechanisms of Action and Resistance to CDK4/6 Inhibitors in Breast Cancer
Abstract
Background: Hormone receptor-positive/HER2-negative breast cancer represents the largest subtype of breast cancer, and for decades the treatment of the disease focused on hormonal therapy. However, a large cohort of patients ends up acquiring resistance, especially patients who present with metastatic disease. Recent advancements in non-hormonal targeted therapies [mTOR and cyclin-dependent kinase 4/6 (CDK4/6) blockade] have proven successful to delay progression when added to hormonal therapy; however, no improvement in overall survival has been observed to date. Virtually all patients eventually exhibit progression and about one-third never respond, or progress within less than 4-6 months. The use of the approved CDK 4/6 inhibitor palbociclib also results in neutropenia, necessitating treatment delay or discontinuation. Also, there are no predictive biomarkers to identify tumors with intrinsic and/or acquired resistance to palbociclib. To eliminate the limitations of this therapy, I have examined dose-dependent effects of palbociclib and unraveled a novel link between autophagy, “self-eating,” and CDK inhibition. Overarching Challenges: I will address the following overarching challenges facing breast cancer patients: (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. (2) Conquer the problems of overdiagnosis and overtreatment. (3) Eliminate the mortality associated with metastatic breast cancer. Various studies have tried to understand the mechanism of the CDK4/6 inhibitors, but no study to date examined the dose-dependent effect of the inhibitor. My preliminary data suggest that inhibition of autophagy could allow lower doses of palbociclib, which could augment its overall benefit with little or no added toxicity and at low cost. In addition, the impact of this approach on cell cycle biology could inform additional therapeutic strategies and improve personalization of therapy. To further understand the dose-dependent mechanisms of the CDK4/6 inhibitors, I will first identify proteins in the autophagy pathway that are direct targets of CDK4/6. Second, I will closely examine the mechanisms of palbociclib resistance to identify treatment strategies to circumvent the acquired resistance. Advancement in Research: The basis for acquired resistance to CDK4/6 inhibitors in the clinic remains largely unknown. Patients who experience resistance to this class of agents are likely to have a less favorable biology (including resistance pathways), requiring novel combination strategies to delay progression and improve survival. Applicability and Clinical Impact: The successful completion of these preclinical studies will provide the rationale to definitively test and translate my proposed novel combination therapies to overcome endocrine resistance and positively impact survival in patients. Pathway to a Patient-Related Outcome: I have two pathways to clinical application: (1) Identification of biomarkers of resistance: Examine the modulators and downstream effectors of palbociclib resistance using tumor specimen from patients who have progressed while on CDK4/6 inhibitors. I will interrogate the deregulated expression of key proteins in the different resistance pathways I have already identified in the in vitro model system. (2) Novel treatment strategies: The in vitro and in vivo preclinical efforts on identifying the best combination treatment strategies for the resistant cells, coupled with biomarker identification in patient samples, will provide the needed pre-clinical data to propose novel clinical trials to our collaborators in Breast Medical Oncology and Investigational Cancer Therapeutics at MD Anderson Cancer Center for breast cancer patients who are likely to develop resistance to the CDK4/6 inhibitors. Researcher Development Plan: My long-term career goal is to engage in translational research that applies basic rese
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810038
Entities
People
- Nicole M Kettner
Organizations
- United States Army
- University of Texas at Austin