PHILADELPHIA (August 30, 2022)—Researchers at Fox Chase Cancer Center have discovered that the drug efflux pump MDR1 promotes resistance to a promising new class of drugs called PROTACS—proteolysis-targeting chimeras.
However, the researchers also found that in cultured cancer cells and mouse models, this resistance was prevented by combining PROTAC treatment with the drug lapatinib, which blocks MDR1 efflux pumps and also inhibits the epidermal growth factor receptor, a frequent oncogene and cause of resistance to cancer drugs.
“The hope is to have a double-pronged effect,” said James S. Duncan, PhD, associate professor in the Cancer Signaling and Epigenetics research program at Fox Chase. “By combining lapatinib with a PROTAC drug we would have the ability to block MDR1-mediated resistance and the epidermal growth factor receptor with a single agent and allow patients to more fully benefit from treatment with PROTAC drugs.”
PROTACS are a promising new class of drugs known as protein degraders because they destroy target proteins in cells using the proteasome degradation pathway. PROTACs have two functional ends. One end engages an E3 ubiquitin ligase and the other a disease-causing protein called a protein of interest or oncogene. By connecting to the ubiquitin ligase, the PROTAC marks the protein for destruction.
“You highjack the cancer cell’s own proteasome machinery to degrade the oncogene,” Duncan said. “This is important because there are a lot of protein targets that are considered to be beyond treatment with traditional inhibitors.”
Cancer cells have an ability to eventually evade the effects of drugs, so targeted cancer therapies, no matter how effective they are initially, will likely encounter resistance. To discover what might drive PROTAC resistance, Duncan and colleagues systematically exposed cancer cells to PROTACs.
Using proteomics, the global analysis of proteins in cells, they identified a specific protein called MDR1 that was increased dramatically in the cells that acquired resistance to PROTACS. “Cancer cells upregulated MDR1 and this protein pumped PROTACS out of the cell, limiting the amount of drug within the cancer cell,” Duncan said.
Interestingly, upregulation of MDR1 has been linked to resistance to other anticancer drugs as well, including chemotherapy. In addition, there are several cancer types that naturally have cells that overexpress—produce high levels—of MDR1 that would likely have intrinsic resistance to PROTACs.
Duncan said that although there are existing small molecule inhibitors for drug efflux pumps like MDR1, they have not shown great success in clinical trials. There are some protein kinase inhibitors like lapatinib that are currently used to treat cancers and have a dual function that allows them to inhibit a kinase and the activity of the drug efflux pump.
Using cell lines from colorectal cancer that overexpress MDR1, Duncan and colleagues found that PROTACs targeting either the protein kinase MEK1/2 or the GTPase KRAS only worked when combined with lapatinib. In mouse models, the combination of MEK1/2 PROTACs with lapatinib improved inhibition of KRAS-mutant colorectal cancer samples that overexpressed MDR1 compared with either agent alone, and also prevented PROTAC resistance.
“This is important because there are a number of cancers that are driven by KRAS and/or MEK1/2 and have high levels of the MDR1 efflux pump,” Duncan said.
Based on these results, concurrent blockade of MDR1 will likely be needed to achieve a durable benefit from PROTACs. Future clinical trials should explore PROTACs in combination with lapatinib, particularly in those cancers that rely on epidermal growth factor receptor, Duncan said.
The article, “The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells,” was published in Science Signaling.