LAUSR

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. Description Lapatinib may boost the efficacy of protein-degrading drugs by blocking drug efflux pumps. Breaking down resistance to degraders Drugs called PROTACs trigger the degradation of their targets, making them attractive strategies for treating cancer. However, Kurimchak et al. found that cancer cells developed resistance to PROTACs as they do to other anticancer drugs. Resistance to PROTACs targeting the GTPase KRAS or pathway-associated proteins MEK, CDK9, FAK, or BRD4 was mediated by the drug efflux protein MDR1, either through intrinsically high abundance of MDR1 or through drug-induced production of MDR1. However, in both cultured cells and mouse models, drug resistance was prevented by combining PROTAC treatment with lapatinib, a small-molecule inhibitor of epidermal growth factor receptors and of the production and/or function of MDR1. The findings suggest that PROTACs in clinical trials should be explored in combination with lapatinib, which is already clinically approved for some cancers.