Analysis of Mechanisms Associated with Her2-Positive Breast Cancer Resistance to Therapy
Abstract
Breast cancer is the most common invasive cancer in women, accounting for more than 40,000 deaths in the United States per year. The Her2-positive subtype comprises approximately 20% of all breast cancers and is defined as displaying overexpression of the human epidermal growth factor receptor 2 (Her2) protein or amplification of the Her2 gene, resulting in increased cell growth and proliferation. While targeted Her2 inhibition, which has been the standard of care for Her2-positive breast cancer since the Food and Drug Administration approval of trastuzumab (TRA, trade name Herceptin), has proven largely effective for the treatment of Her2-positive breast cancers, approximately half of all patients either do not respond to treatment or respond initially but eventually acquire secondary resistance. One known molecular mechanism underlying some forms of anticancer drug resistance involves the upregulation of alternative receptor tyrosine kinases (RTKs), which can function to bypass targeted inhibition. RTKs have the advantage of being viable therapeutic targets, and these types of bypass resistance mechanisms have been observed in other cancer types including lung cancer and melanoma. However, it is currently unclear which specific receptors can drive resistance to Her2 inhibition in breast cancer, as a comprehensive study of all RTKs associated with drug resistance in Her2-positive patients has not been performed. To address this issue, we have undertaken an unbiased bioinformatic analysis of the expression of 49 human RTKs as it relates to Her2 breast cancer patient survival using a database composed of 22 publicly available datasets. Of the RTKs in which high expression was associated with poor patient survival, three receptors (IGF1R, TYRO3, and PDGFRb) were able to functionally confer drug resistance when overexpressed in Her2-positive breast cancer cells. Moreover, using a panel of Her2-positive breast tumors, we observed that the expression of these three RTKs was specifically elevated only in patients who failed to respond to TRA therapy. In addition, combinational inhibition of IGF1R or PDGFRb together with Her2 was found to impede cell proliferation in vitro by producing a state of stable growth arrest, termed cellular senescence, which was also observed in patient tumors that responded to TRA therapy. Thus, cellular senescence likely represents an important biological process underlying the clinical efficacy of Her2 inhibition. To further our understanding of the biological pathways mediating Her2 inhibitor activity and also explore the potential therapeutic utility of these findings, we propose two specific aims: (1) Evaluate therapeutic efficacy and explore underlying mechanisms associated with targeted inhibition of RTKs mediating resistance to Her2 inhibition in breast cancer. (2) Use unbiased genomic editing technology to discover and characterize novel molecular targets for TRA-resistant breast cancer. We believe that this proposed research will address at least three overarching challenges specified for the Breast Cancer Research Program Breakthrough Award: (1) Identify what drives breast cancer growth and determine how to stop it, since we will uncover the roles of several RTKs that can functionally compensate for the loss of Her2 activity and also develop ways to interfere with their activities associated with resistance to therapy. (2) Revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. Our research will lead to the development of new combinational therapies that could reduce the dosages of individual drugs and their associated side effects to effectively treat Her2-positive breast cancer. (3) Eliminate the mortality associated with metastatic breast cancer. Her2-positive breast cancer often develops into metastasis with high mortality for those who exhibit a drug-resistant phenotype. Thus, our re
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610618
Entities
People
- Xiao-Fan Wang
Organizations
- Duke University
- United States Army