Monthly Publication Highlight - Dr. Michael Wendt
December 2016 - The Purdue College of Pharmacy is pleased to honor and recognize the outstanding research and scholarship generated by our faculty each month. This month we highlight Dr. Michael Wendt, Assistant Professor of Medicinal Chemistry and Molecular Pharmacology. Dr. Wendt’s recent publication, “FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition,” can be read in Oncotarget (DOI: 10.18632/oncotarget.13117, November 4, 2016). These studies were completed in collaboration with Dr. Wells Brown, a postdoctoral fellow in the Wendt Lab, and Saeed Salehin Akhand, a graduate student in the Wendt lab. This work was conducted within the Purdue Center for Cancer Research in the Hansen Life Sciences Research Building and was supported in part by funds from the Purdue College of Pharmacy, National Institutes of Health, and the METavivor foundation.
Twenty-five percent of breast cancers overexpress the proto-oncogene human epidermal growth factor receptor 2 (Her2). This has led to the development of several therapeutic antibodies, antibody-drug conjugates, and kinase inhibitors that antagonize the action of this critical tumor driver. These therapeutics have changed the face of Her2+ breast cancer, but with the increased specificity and decreased toxicity of these personalized medicines comes the drawbacks of acquired and inherent resistance. Indeed, a major subset of Her2+ breast cancer patients either don’t respond to these drugs or respond only to relapse with drug-resistant disease. In this study we are examining the mechanisms that drive the resistance to a clinically used Her2-kinase inhibitor, Lapatinib. We developed a cell model that was originally sensitive to Lapatinib, but prolonged application of the drug led to the emergence of a drug-resistant cell population. Establishment of these matched drug sensitive and resistant breast cancer cells allowed for direct genetic characterization to identify potential drivers of drug resistance. This genetic characterization pointed to enhanced expression and activity of an alternate growth factor receptor called fibroblast growth factor receptor (FGFR). Using a novel FGFR inhibitor that we recently developed in collaboration with Dr. Nathanael Gray at the Dana-Farber Cancer Institute, we were able to demonstrate that as cells become resistant to Her2 inhibition they become increasingly sensitive to FGFR inhibition.
“This work exemplifies the fundamental interests of our lab by demonstrating the plasticity of aggressive breast cancer cells,” comments Dr. Wendt. “Through a combination of cell selection and phenotypic transitions, tumor populations are able to efficiently switch from one driver pathway to another. With the recent development of this novel compound and other FGFR inhibitors now entering clinical trails we are very excited to move forward in contributing to the development of a therapy combining Her2 and FGFR-targeted drugs. This work is support by our recent crowdfunding project where we are establishing novel patient-derived models of Her2+ disease. With these new models in hand we will be able to optimize a combination protocol, and begin to establish which patients will most benefit from FGFR/Her2+ therapy. Our hope is that this ‘one-two punch’ will improve and prolong response times for Her2+ breast cancer patients.”