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

ABSTRACT: PROTACs (Proteolysis-Targeting Chimeras) represent a revolutionary 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 protein degraders remains poorly understood. Here, we applied proteomics approaches to elucidate resistance mechanisms to protein degrader therapies in cancer cells. Our studies revealed acquired resistance to degrader therapies in cancer cells can be mediated by upregulation of the ATP-dependent drug efflux pump MDR1. Degrader-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, MDR1 is frequently overexpressed in cancer, and cancer cell lines overexpressing MDR1 exhibited intrinsic resistance to protein degraders, requiring co-treatment with MDR1 inhibitors to achieve protein degradation and therapeutic response. Notably, co-treatment of MDR1-overexpressing K-ras mutant colorectal cancer cells with MEK1/2 or K-ras degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 activity and ErbB receptor-driven resistance. Together, our findings showed overexpression of MDR1 can promote both intrinsic and acquired resistance to protein degraders in cancer cells and that concurrent blockade of MDR1 will likely be required to achieve durable protein degradation and therapeutic response.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Colon Cancer,Malignant Neoplasm Of Ovary,Breast Cancer

SUBMITTER: James Duncan  

LAB HEAD: James Duncan

PROVIDER: PXD029233 | Pride | 2022-10-06

REPOSITORIES: Pride