Date: June 22 2023
Presenter(s): James Duncan, PhD
Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1 (which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRASG12C synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.
About the presenter:
Associate Professor, Cancer Biology at the Fox Chase Cancer Center
Dr. James S. Duncan is an Associate Professor of Cancer Biology at the Fox Chase Cancer Center. He received his PhD from the University of Western Ontario, then performed his postdoctoral fellowship in the Department of Pharmacology at the University of North Carolina. There he developed a proteomics strategy that provides a systems biology platform to profile global kinome activity in any cell line or tumor biopsy.
Dr. Duncan’s laboratory at Fox Chase applies similar proteomics approaches to explore drug resistance mechanisms in several cancer models. He has received numerous accolades for his work, including research awards from the Sandy Rollman Ovarian Cancer Foundation, the Ovarian Cancer Research Alliance, the American Cancer Society, and the NIH.