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

Abstract

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.

Cooperatively Designed Aptamer-PROTACs for Spatioselective Degradation of Nucleocytoplasmic Shuttling Protein for Enhanced Combinational Therapy

“…In addition, drug synergy of PS-ApTCs and ApDCs was evaluated using the Bliss independence model, 68,69 which showed an average synergistic effect greater than 15%, in a dosage range of 50-400 nM for PS-ApTCs and ApDCs, suggesting a synergistic effect (Figure 4C). A Bliss synergy score was determined as 19.1 (Figure S28), which is comparable to that of previous combination of BET protein degraders and MDR1 inhibitors, 70 suggesting a synergistic effect. Additionally, an antagonistic interaction was identified between drugs of Control-PS-ApTCs and ApDCs (Figure S29).…”

PROTACs: past, present and future

“…Upregulation of the drug efflux pump MDR1 has also been reported to mediate intrinsic and acquired resistance to PROTACs in cancer cells. 152 Co-treatment with MDR1 inhibitors and PROTACs resulted in durable POI degradation even in cells with upregulated MDR1 expression.…”

“…Upregulation of the drug efflux pump MDR1 has also been reported to mediate intrinsic and acquired resistance to PRO-TACs in cancer cells. 152 Co-treatment with MDR1 inhibitors and PROTACs resulted in durable POI degradation even in cells with upregulated MDR1 expression. Targeting virus-related proteins/RNA As with cancer chemotherapy, a major challenge in antiviral drug development is the emergence of drug resistance.…”

Targeting Protein Kinases and Epigenetic Control as Combinatorial Therapy Options for Advanced Prostate Cancer Treatment

“…PROTACs bind to proteins of interest and use E3 ligase to degrade the entire target protein via the ubiquitin–proteasome pathway [ 59 ]. However, as with other methods, PROTAC technology faces challenges, such as acquired and intrinsic resistance to drugs in cancer cells [ 60 ]. The use of natural products and probiotics are other tools that have been considered as potential kinase inhibitors in recent years.…”