Capitalists have been interested in proteolysis targeting chimeric (PROTAC) technology, in part because of its mechanistic potential to prevent drug resistance and catalytically trigger degradation of target proteins. However, it has been hypothesized that PROTAC might cause E3 ligase mutations, which would result in drug resistance.
Recent studies from the Chase Fox Cancer Center have demonstrated that the drug efflux pump MDR1 can cause PROTAC to become resistant to drugs, and that using lapatinib in combination with PROTAC can prevent PROTAC resistance in both cellular and animal models. On August 30, the study was released as the journal Science Signaling's cover article.
PROTAC drives the catalytic degradation of target proteins by the ubiquitin-proteasome by simultaneously binding to key tumor target proteins and E3 ligases, leading to tumor cell death. James S. Duncan, corresponding author of the article, said, "Degrading cancer proteins by hijacking the tumor cell's own proteasome is important because many protein targets are traditionally considered beyond the targeting range of conventional inhibitors." However, tumor cells are very cunning and have an innate ability to evade the killing effects of drugs. Thus, no matter how effective an antitumor drug is initially, resistance may eventually develop.
To discover what might be causing PROTAC resistance, the researchers performed proteomic analysis after exposing tumor cells to PROTAC and found that the MDR1 protein was significantly increased in PROTAC-resistant tumor cells. Duncan said, "Cancer cells upregulate MDR1, a protein that pumps PROTAC out of the cell, limiting the amount of drug in the cell."
Previous studies have shown that MDR1 upregulation is also associated with resistance to other antitumor drugs, such as chemotherapeutic agents. In addition, some tumor cells that naturally overexpress MDR1 may be naturally resistant to PROTAC, Duncan said, adding that drugs that target the MDR1 protein in the clinic have not yielded very exciting results in clinical trials. Lapatinib, currently used in the clinic to treat tumors, inhibits both epidermal growth factor kinase activity and the drug efflux of MDR1.
In colorectal cancer cell lines overexpressing MDR1, researchers found that PROTAC, which targets the protein kinase MEK1/2 or GTPase KRAS, had antitumor activity only when combined with lapatinib. In a mouse model, MEK1/2 PROTAC in combination with lapatinib inhibited KRAS-mutated colorectal cancer samples overexpressing MDR1 significantly better than when used alone, while also avoiding PROTAC resistance.
Duncan said that because many cancers are driven by KRAS and/or MEK1/2, they also express high levels of MDR1 efflux proteins. Therefore, in future clinical trials, particularly in indications that rely on the epidermal growth factor receptor, the drug combination of PROTAC and lapatinib needs to be explored to block the efflux of MDR1 to PROTAC for patients to derive lasting benefits from PROTAC.
