Mismatch Repair Loss Renders ER+/HER2- Breast Cancer Susceptible to HER2/3 Inhibition
Abstract
Background and Rationale: More than 40,000 women will die of breast cancer this year in the United States. Most of these women are diagnosed with estrogen receptor (ER+) breast cancer and are treated with endocrine therapy. Unfortunately, more than one-third of all ER+ tumors, and one-half of all metastatic ER+ tumors are inherently endocrine therapy-resistant. There are few known drivers of intrinsic endocrine therapy resistance. We recently discovered that loss of mismatch repair, a type of DNA repair mechanism, induces resistance to endocrine therapy. Loss of mismatch repair occurs in 27% of endocrine therapy-resistant tumors (7-10,000 women/year). Critically, we need to identify therapeutic combinations that can help women whose tumors have lost mismatch repair have better clinical outcomes. From preliminary investigations, we find that loss of mismatch repair activates HER2 and HER3 signaling. HER2/3 are known oncogenes that have previously been implicated in endocrine therapy resistance. However, clinical trials targeting HER2 in endocrine therapy-resistant patient tumors had mixed success. This is likely because there are no known stratifiers to identify tumors most likely to respond to HER2 inhibition. We believe that mismatch repair loss could be a stratifier. Objective and Aims: The objective of this proposed study is to investigate a role for HER2/3 upregulation in driving the growth and treatment resistance of mismatch repair-defective ER+ tumors and is based on the hypothesis that mismatch repair defects can trigger HER2/3 activation and predict sensitivity to HER2 inhibitors. To test this hypothesis, we will first confirm our preliminary findings that mismatch repair loss in ER+ breast cancer cells can activate HER2/3 using cell line and patient derived xenografts, and patient tumors (Aim 1). Next, we will uncover the mechanisms by which mismatch repair loss can activate HER2/3 using two screens (Aim 2). The first will use our novel drug bead proteomics approach where we use clinically relevant drugs (in this case a HER2 inhibitor) as bait to specifically lure proteins that are targeted by the drug that we hope to treat patients with. We then examine the lured proteins to find differences in their composition that can provide clues to optimize treatment of patients with mismatch repair defective breast cancer. The second screen will look at the “secretome.” Proteins produced by the cell and secreted into its surroundings can affect the composition of growth factors (like HER2) on the cell surface. By assaying all the proteins secreted by the cell, we can identify one way in which mismatch repair loss changes a breast cancer cell’s ability to respond to HER2 inhibitors. Finally, we will validate the ability of HER inhibitors to stop ER+ breast cancer cells with poor mismatch repair from growing (Aim 3). The overarching Breast Cancer Research Program challenge addressed by this study is to “Revolutionize treatment regimens by replacing them with those that are more effective and less toxic.” Who This Project Will Help: This study will primarily help the >30,000 women with ER+ breast cancer who are inherently resistant to standard-of-care endocrine therapy every year in the US. Potential Clinical Applications: The results of this study will provide clinicians with a way to identify patients most likely to respond to HER2 inhibitors at diagnosis. Instead of treating every patient as equal and either over- or under-treating her, the results of this study will enable the clinician to identify, in advance, women who require additional intervention, and provide personalized therapeutic alternatives. Time to Patient-Related Outcomes: Since we aim to reposition HER2 inhibitors that are already in common clinical use, with the support of our collaborator, Dr. Matthew Ellis, the projected time to patient-related outcomes is short (3 years). Impact on Ending Breast Cancer: At even a c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810034
Entities
People
- Svasti Haricharan
Organizations
- Baylor College of Medicine
- United States Army