Rational Targeting of TTK/MPS1 in HER2-Negative Breast Cancer
Abstract
Breast cancer is the most frequently diagnosed cancer in women. HER2-negative breast cancers do not express high levels of HER2 protein and do not respond to agents that target HER2. In recent years a kinase protein called TTK has emerged as a promising target in HER2-negative cancers. TTK is overexpressed in cancers compared to normal tissues, and controls the proper separation of DNA into daughter cells during cell division. TTK inhibitors are in current clinical trials against HER2-negative breast cancer. However, some cancers respond to TTK inhibitor treatment while others do not, and there is currently no way to identify those tumors that will or will not respond. To address this problem, we examined gene expression patterns in breast cancer cells that do or do not respond to TTK inhibitor treatment. Remarkably, from this analysis we identified a four-member gene set that associates with sensitivity to TTK inhibitor treatment. High expression of these four genes identifies breast cancer cells that are sensitive to TTK inhibitor treatment, while low expression of these genes identifies breast cancer cells that are resistant to TTK inhibitor. The goals of this grant are (1) to test if this gene set can predict sensitivity to TTK inhibitors in a large panel of HER2-negative breast cancer cell lines and tumors, and (2) to determine the mechanisms involved. The potential impact of these studies is tremendous. Validation of this predictive gene set could provide clinicians with a tool for personalized medicine. Specifically, by examining this gene set clinicians could identify a priori patients that would or would not respond to TTK inhibitors, and adjust their treatment plans accordingly. In terms of the overarching challenges, the proposed studies would revolutionize treatments, reduce overtreatment, and improve survival. We expect that this project will lead to clinical validation of the gene signature as predictive biomarker in the next 3 to 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210134
Entities
People
- Carl G. Maki
Organizations
- Rush University Medical Center
- United States Army