ABCC1 Becomes A Key "Barrier" for Cancer Cells to Resist PROTAC Treatment

In the field of cancer treatment, proteolysis targeting chimeras (PROTACs) are gradually emerging as a new generation of drugs. This type of drug can accurately target and degrade proteins closely related to cancer growth, bringing hope for conquering those "undruggable" targets that are difficult to deal with with traditional drugs, and also opening up new treatment pathways for many diseases that have no effective treatment options. However, the intracellular transport mechanism of PROTACs, especially what factors affect its therapeutic effect in cancer cells, has always been a mystery that researchers are eager to solve.

Recently, a study published in Cell Chem Biol, titled "The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells", conducted an in-depth study on this, aiming to find out the cellular factors that affect PROTAC activity. They constructed a CRISPR-Cas9 gene knockout library and a cDNA overexpression library for transporters, comprehensively screened a variety of cancer cell lines, and used advanced technologies such as metabolomics for in-depth analysis.

ABCC1 has been clearly identified as the main PROTAC resistance factor in cancer cells. In the screening experiment for MZ1 and related PROTACs, the single guide RNA (sgRNAs) corresponding to the ABCC1 gene was significantly lost. After overexpressing ABCC1 cDNA, the resistance of cancer cells to MZ1 was significantly enhanced. This result strongly proves that ABCC1 plays a key role in the PROTAC efflux process.

Further studies revealed the specific mechanism by which ABCC1 affects the efficacy of PROTAC. ABCC1 does not directly efflux intact MZ1, but effluxes its hydrolysis products. In ABCC1 gene knockout cells, the effective concentration of MZ1 is greatly reduced, and the accumulation of MZ1 and its hydrolysis product MZ1_met in the cells is significantly increased. At the same time, the excretion rate of MZ1_met in ABCC1 knockout cells is significantly slowed down. Combining these experimental results, it can be concluded that ABCC1 reduces the bioavailability of PROTAC by effluxing the hydrolysis products of MZ1, thereby limiting its effect on cancer cells.

The effect of ABCC1 on PROTAC sensitivity varies in different cancer cell lines. In most cancer cell lines, the expression of ABCC1 is much higher than that of ABCB1. Taking the HCT116 cell line as an example, its ABCB1 expression is low. After ABCC1 gene knockout, the cell resistance to MZ1 is significantly reduced. In the LS180 cell line with similar expression levels of ABCB1 and ABCC1, there is functional redundancy between the two, which jointly affects the clearance of PROTAC.

In addition, ABCC1 has different effects on PROTACs with different structures. It has drug resistance to a variety of BET degradation PROTACs, but has no obvious clearance effect on some structurally unrelated PROTACs, such as ACBI1 and BI-3663. In the whole genome drug resistance screening, in addition to further confirming known drug resistance factors such as ABCB1, some genes related to processes such as ubiquitination, mTOR signaling pathway and cell apoptosis were also found. These genes are also involved in the PROTAC resistance process.

Figure 1. The transporter ABCC1 is a major PROTAC resistance factor in human cancer cells.(Wolf G, et al., 2025)

This study successfully revealed that ABCC1, as a key efflux pump, continuously limits the sensitivity of various cancer cells to PROTAC, providing an important basis for understanding the transport mechanism and drug resistance of PROTAC in cancer cells. Although the introduction mechanism of PROTAC has not yet been clarified, this study has pointed out the direction for subsequent exploration of how to optimize the PROTAC structure and overcome drug resistance. It is expected to promote the widespread application of PROTAC in clinical treatment and bring new breakthroughs to cancer treatment.