Bioinformatic analysis of fibroblast-mediated therapy resistance in HER2+ breast cancer Jacob C. McDonalda and Ioannis K. Zervantonakisa, b Tumor Microenvironment Engineering Laboratory, Department of Bioengineering, bUPMC Hillman Cancer Center
a
Jacob McDonald is a junior bioengineering student at the University of Pittsburgh with a focus in cellular engineering. After graduating, he plans to further his education and bioengineering research by attending graduate school. Jacob C. McDonald
Ioannis Zervantonakis is an Assistant Professor at the Department of Bioengineering, University of Pittsburgh and at the Hillman Cancer Center UPMC. He serves as an Early-Career Associate Scientific Advisor to Science Translational Medicine, has received the 2020 Hillman Early-Career Fellow Ioannis K. for Innovative Cancer Research Award Zervantonakis and his laboratory is funded by an Elsa Pardee Foundation Award.
Significance Statement
Interactions between tumor cells and stromal fibroblasts in the tumor microenvironment have been shown to mediate drug resistance in some HER2 overexpressing breast cancers. This study identifies signaling pathways within tumor cells that are critical to fibroblast-mediated drug resistance and proposes targeting specific proteins to restore treatment sensitivity.
Category: Computational Research
Keywords: breast cancer, tumor microenvironment, fibroblasts, drug resistance
60 Undergraduate Research at the Swanson School of Engineering
Abstract
Multiple targeted therapies have been developed for the treatment of HER2 overexpressing (HER2+) breast cancers, such as the dual HER2/EGFR kinase inhibitor lapatinib, but many patients eventually develop resistance to these treatments. One proposed cause of HER2 therapy resistance is the interaction between tumor cells and stromal fibroblasts in the tumor microenvironment, which has been reported to activate signaling pathways in HER2+ tumor cells that lead to a decrease in drug sensitivity. Here, we identify and compare both protein-expression and gene-expression signatures of breast cancer cells that exhibit fibroblast-mediated lapatinib resistance. We then integrate proteomic data with cell treatment response data to identify optimal protein targets for combination therapy that may restore lapatinib sensitivity in fibroblast-protected cancer cells. Our signatures for fibroblast protection suggest that fibroblasts reduce lapatinib sensitivity in HER2+ breast cancer cells through reactivation of the PI3K/Akt and mTOR signaling pathways, which results in increased cell cycle signaling and changes in lipid metabolism. Specifically, we found that lapatinib resulted in greater inhibition of proteins in the Akt/mTOR, cell cycle, and lipid synthesis pathways in cell lines that exhibited high sensitivity to lapatinib (i.e. low cell viability). Together, our findings suggest that inhibition of these pathways may be sufficient to restore lapatinib sensitivity in fibroblast-protected breast cancer cells.
1. Introduction
HER2 overexpressing (HER2+) breast cancer accounts for ~20% of all breast cancer cases [1]. The HER2 receptor is a receptor tyrosine kinase in the epidermal growth factor receptor family (ErbB), and heterodimerization of HER2 with other members of the ErbB family leads to signal transduction through the PI3K/Akt and MAPK survival pathways [2]. As a result, overexpression of HER2 can lead to increased cancer cell survival, proliferation, and invasion. Multiple targeted therapies have been developed to treat HER2+ breast cancer, such as the dual HER2/ EGFR kinase inhibitor lapatinib. Lapatinib acts by binding to the kinase domain of the HER2 receptor, preventing its autophosphorylation and therefore its ability to transduce pro-survival signaling [3]. However, even though lapatinib treatment may initially be successful in treating HER2+ breast cancers, many patients will eventually develop resistance to these treatments. Several mechanisms of resistance to lapatinib treatment have been proposed, such as the activation of compensatory signaling pathways through other kinases, mutation of the HER2 kinase domain, or gene amplification [3]. Another proposed cause of HER2 therapy resistance is the interaction between tumor cells and stromal fibroblasts in the tumor microenvironment, which can occur through direct cell-cell contact or through the secretion of soluble factors. These tumor-fibroblast interactions have been reported to activate signaling pathways in some HER2+ tumor cell lines, such as the mTOR
