Read the article to understand how to understand and manage ADC drug resistance

Article source: Medicine Rubik's Cube Med

Author: leaves

Treatment resistance will always be a hot topic of discussion.

The mechanism of action of ADC: exploring the traceability of drug resistance

Three innovative HER2 ADCs have been marketed globally, namely trastuzumab (T-DM1), Enhertu (T-DXd) and vedicitumab (RC48-ADC)

Cancers 2022, 14, 154 (the same below)

Generally, the mechanism of action of ADC drugs mainly includes the following steps: the antibody in the ADC drug binds to the antigen HER2 expressed on the cell surface, and then the complex formed by ADC-HER2 is internalized through receptor-mediated endocytosis or pinocytosis.

Diagram of the mechanism of action of ADC drugs

However, specific drugs also differ in their mechanism of action based on the properties of the drug

It is not difficult to see that although the mechanism of action of HER2 ADCs is similar and consistent, they are not exactly the same

Resistance mechanisms of ADCs: retrospective based on mechanism of action

After understanding the structure and mechanism of action of ADC drugs, it is not difficult to speculate about the types of drug resistance that can occur: changes in antigen HER2, changes in HER2 internalization, changes in lysosomes, increased expression and activity of drug efflux pumps, Increase the production of ligands and the activation of alternative pathways, changes in signaling pathway proteins,

1.

Still taking T-DM1 as an example, since the antibody in T-DM1 needs to bind to the HER2 protein, when the patient receives the front-line trastuzumab and pertuzumab treatment, the expression level of HER2 may be reduced, while T -DM1 does not have a bystander effect, which reduces the therapeutic effect of T-DM1 as a second-line therapy

A high degree of heterogeneity in HER2 expression was also shown for patients who experienced local progression prior to surgery

2.

When the HER2 ADC binds to HER2, the complex is internalized into the cell, and the endothelin A2 protein facilitates this process

On the other hand, rapid recycling of HER2-containing endosomes to the plasma membrane may slow the rate at which T-DM1 reaches lysosomes

Recently, the internalization of T-DM1 through a pit composed of CAV1, a resistance mechanism that restricts its access to the lysosome, was described

3.

The arrival of HER2 ADCs in the lysosome and the processing of lysosomal enzymes is critical for the release of the antibody-bound payload

In another model of resistance to T-DM1, a reduction in lysosomal acidification was also reported

4.
Increased expression and activity of drug efflux pumps

Increased expression and/or activity of efflux pumps is an important mechanism of chemoresistance
.
It is not difficult to understand that if too much of the payload released in the cell is transferred to the outside of the cell by the efflux pump, especially for Lys-MCC-DM1, a drug that cannot penetrate automatically (similar to the bystander effect), the effectiveness necessarily lower
.

Specifically, altered expression of ABCB1/MDR1/P-gp, ABCC1/MRP1, ABCC2, and ABCG2/BCRP/MXR/ABCP resulted in resistance to T-DM1 in preclinical models
.
In these studies, inhibition of transporter activity restored sensitivity to T-DM1
.

5.
Ligand augmentation and activation of alternative pathways

In fact, this mechanism is more of an alternative signaling pathway and affects the efficacy of the drug
.
In an in vitro study, the effect of T-DM1 was inhibited by HER2/HER3 dimerization and activation of the PI3K/AKT pathway, or by addition of the HER3 ligand neuregulin (NRG) in some HER2-positive cell lines
.

In addition, decreased HER2 levels accompanied by increased EGFR levels in models of acquired resistance to T-DM1 and primary resistance to trastuzumab are also a mechanism of resistance
.
However, EGFR silencing was not sufficient to reverse the drug-resistant phenotype
.
Also, it was observed that increased EGFR levels lead to increased amounts of integrins (α5β1 and αVβ3), resulting in enhanced motility and invasiveness of resistant cells
.

6.
Changes in proteins involved in signaling pathways

This drug resistance mechanism is complex, and different mechanisms will be shown for different loads
.
However, this resistance mechanism is similar to or close to changes in signaling pathways caused by direct use of the load
.

In the case of T-DM1, treatment results in an increase in cyclin B1 and arrest in the G2/M phase of the cell cycle, a process that triggers a mitotic catastrophe phenotype
.
However, this phenomenon was not observed in T-DM1-resistant cells, and no accumulation of cyclin B1 occurred
.

In addition, increased expression of the mitotic kinase, polo-like kinase 1 (PLK1), was also found in models resistant to T-DM1
.
Furthermore, reduced levels of PTEN also resulted in a resistant phenotype, reducing the effects of T-DM1 and trastuzumab
.
At the same time, deletion of PTEN and activating mutations in the gene encoding the catalytic subunit of PI3K (PIK3CA) lead to constitutive activation of the PI3K/AKT pathway, which has also become a resistance mechanism to HER2 receptor therapy
.

Recently, increased resistance to anti-tubulin drugs has been observed in HER2-positive breast cancer cell lines that have acquired resistance to T-DM1
.
These cells had lower levels of polymerized tubulin and βIII tubulin and increased baseline aneuploidy
.
However, silencing of tubulin βIII in the parental line was not sufficient to confer resistance to T-DM1, suggesting that multiple factors may be involved in the cause of resistance, including modification of the microtubule/tubulin complex and chromosomal instability
.

How to manage drug resistance in ADCs

How to manage the drug resistance of ADC drugs, naturally, we must start from the drug resistance mechanism, clarify each drug or the displayed drug resistance pattern and select an appropriate coping strategy
.

For example, for drug efflux pumps, an effective strategy is to replace a drug form that cannot be actively pumped out by the efflux pump, including replacing new ADC drugs with different loadings and coupling technologies or loading modifications, such as maleyl-based The DM1 was replaced by the hydrophilic linker PEG4Mal of the imine, making it Lys-PEG4Mal-DM1, avoiding expulsion
.
Of course, drugs that reduce the activity of the drug efflux pump can also be selected to reduce the efflux of active metabolites
.

Corresponding measures can also be taken in the face of changes in HER2, including internalization, circulation, and dimerization
.
For HER2 recycling, HSP90 inhibitors that inhibit the acceleration of cycling can be added, which can not only reduce HER2 recycling but also induce HER2 localization in intracellular vesicles, thereby improving HER2 degradation
.
For dimer, HER3 antibody or HER2/HER3 bispecific antibody can be used, of course, these drugs are not yet on the market in China
.

Facing the drug resistance of pathway activation, there is relatively more experience and drugs, such as the combined use of small molecule HER2 inhibitors or inhibitors of PI3K/AKT and MAPK/ERK pathways
.
Combination therapy is not only an effective strategy to combat drug resistance, but also a synergistic treatment, and there are many combination therapies in traditional chemotherapy
.
For ADC drugs, small molecule drugs, PD-1/L1 immune drugs, etc.
can also be combined
.

Written at the end: ADC represents a class of drugs with high anti-tumor activity, but the domestic application has not been fully popularized, and the types of drug resistance and experience in dealing with them still need to be accumulated
.
In general, the drug resistance mechanisms of HER2 ADC drugs are diverse, which need to be analyzed in combination with multiple factors such as antibodies, lysosomes, and loading
.
Currently, no further mechanisms of drug resistance have been described for T-DXd or other HER2 ADCs, but it is expected that some of the mechanisms described for trastuzumab, pertuzumab, and/or T-DM1 could be extrapolated to T -DXd and other HER2 ADC drugs using the same antibody or technology
.

references

1.
Cancers 2022, 14, 154.
https://doi.
org/10.
3390/cancers14010154.