New target DDR1: a "double-edged sword" for solid tumors

Up to now, tumor treatment is in a new era
of continuous optimization and innovation from traditional surgery, radiotherapy, chemotherapy, molecular targeted therapy, cell immunotherapy, collaborative therapy, etc.
In the revolutionary wave of continuous development of immunotherapy, immune cell-based therapy is currently one of
the hottest and most cutting-edge research areas in cancer treatment.
In this context, finding a new solid tumor target with strong specificity and high sensitivity is a key part of optimizing the treatment of
cancer by cellular immunotherapy.

DDR structure and normal function

DDR is a collagen-activated RTK discovered in the 90s of the 20th century, and DDR2 has only one subtype
.
The molecular structure of DDR consists of
intracellular kinase domains, transmembrane domains, and extracellular domains.
DDR binds to collagen, one of the most abundant proteins in the extracellular matrix, and stimulates DDR phosphorylation to activate kinase activity
.

Figure 1.
Structure and subtypes of DDR1 and DDR2

• Expression profile of DDR1 in human tissues

At the single-cell level, DDR1 is mainly expressed on airway epithelial cells-mucosa, and DDR1 expression is not distributed
in immune cells.

Figure 2.
Distribution of DDR1 in human single cells

Solid tumor tissue consists of
the parenchyma and interstitium.
The tumor parenchyma is mainly composed of
tissue-specific tumor cells.
In addition to tumor cells, another component that makes up TME is the stroma
.
The relationship between DDR1 and tumor cells includes tumor cell proliferation, differentiation, migration, invasion, intercellular adhesion, epithelial mesenchymal transformation, apoptosis, energy metabolism, etc.
, while the relationship between DDR1 and tumor microenvironment includes immune cells, mesenchymal cells, blood vessels, lymphatic vessels, collagen, etc
.

In terms of tissue morphogenesis, previous breast ductal morphogenetic studies have found that cells overexpressing DDR1a and DDR1b form shorter tubules and fewer branches
in collagen gel.
In addition to the critical role of DDR1 in breast cancer development, one study found that in pancreatic ductal adenocarcinoma, DDR1-/- model mice had increased acinar cell shedding and increased fibrous collagen deposition to maintain tissue homeostasis
.

In tumor cell production, the effect of DDR1 on IGF-2/IR-A ring and cell differentiation was evaluated in undifferentiated human thyroid cancer cells, and it was found that DDR1 silencing or down-regulation led to a significant decrease in IR-A and IGF-2 expression, and an increase
in differentiation markers (NIS, Tg, TSH, TPO).
Conversely, changes induced by DDR1 or its kinase inactivation variant K618A DDR1 indicate hypodifferentiation and overexpression
of the stem-like phenotype.

In terms of cancer cell proliferation, DDR1 affects the signaling pathways of cancer cell proliferation are different
.
Emerging data in recent years suggest that DDR1 can affect the ability
of tumor cells to invade and migrate.

Drugs that target DDR1

DDR1 may be one of the
new targets of tumor immunotherapy.
Therefore, understanding the future development status of global drugs and antibodies targeting DDR1 is of great significance
for clinical treatment.
Most DDR1-targeting drug therapies are in oncology, with 4 of the 8 global drug clinical trials targeting DDR1 being conducted in solid tumors
.
These studies reflect the accelerating development of DDR1-targeting drugs and antibodies that may hold new promise
for cancer patients.

Table 1.
Global drug discovery for DDR1

Table 2: Development of antibodies targeting DDR1

With the rapid development of artificial intelligence and deep learning, more and more DDR1 kinase inhibitors have been rapidly identified, which will greatly promote DDR1 kinase inhibitors to play a greater role
in solid tumors.
In addition, a previous study found that anti-DDR1 monoclonal antibody can inhibit the immune rejection of solid tumors, opening up a new pathway
for tumor immune matrix therapy.
In addition to the above-mentioned drugs and antibodies against DDR1, a large number of studies have confirmed that CAR-T cells have completely changed the treatment pattern of hematologic malignancies, but CAR-T cells still face many challenges
in the treatment of solid tumors.
The search for highly specific tumor antigens is one of
the strategies to overcome the above challenges.
Here, based on the unique role of DDR1 in the development and development of solid tumors and the challenges faced by CAR T cells in the treatment of solid tumors, we can kill cancer cells by releasing cytotoxic factors in the future to prepare CAR-T cells targeting DDR1, and the development of DDR1-targeting CAR-T cells to treat solid tumors will be a very interesting and challenging task
.
Based on the unique role of DDR1 in tumors, it is likely to exert a powerful anti-tumor effect
.

Figure: Targeting DDR1-CAR-T cells to kill cancer cells

conclusion

In summary, the new target DDR1 is a "double-edged sword"
for solid tumors.
Because it is closely related
to the pathogenesis and prognosis of solid tumors.
In addition, with the rapid development of artificial intelligence and big data, drugs targeting DDR1 are rapidly being discovered and gradually moving towards the clinic, which may have a transformative impact
on the treatment of solid tumors.
Therefore, we have reason to believe that the new target DDR1 gene will strongly promote the treatment
of solid tumors in the near future.

Tian Y, Bai F, Zhang D.
New target DDR1: A "double-edged sword" in solid tumors.
Biochim Biophys Acta Rev Cancer.
2022 Nov 7; 1878(1):188829.
doi: 10.
1016/j.
bbcan.
2022.
188829.
Epub ahead of print.
PMID: 36356724