MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

PROTACs (Proteolysis-Targeting Chimeras) represent a promising new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to PROTACs remains poorly understood. Using proteomics, we discovered acquired and intrinsic resistance to PROTACs in cancer cells can be mediated by upregulation of the drug efflux pump MDR1. PROTAC-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, co-treatment of MDR1-overexpressing colorectal cancer cells with MEK1/2 or KRASG12C degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 and ErbB receptor activity. Together, our findings suggest that concurrent blockade of MDR1 will likely be required in combination with PROTACs to achieve durable protein degradation and therapeutic response in cancer.