CDCP1: A Key Mediator for Cell Signaling in Cancers, an Emerging Target for Anti-Tumor Drugs!

1. What is CDCP1?

1.1 CDCP1 Structure

CUB-domain containing protein 1 (CDCP1), also called CD318, SIMA135, gp140, or TRASK, is a type I transmembrane glycoprotein. Discovered via cDNA microarray technology by Scherlmostageerm et al. in 2001, it's a novel human tumor-associated gene. CDCP1's full form includes 836 amino acids, with a 29-amino acid signal peptide, extracellular, transmembrane, and cytoplasmic domains. The extracellular part features three CUB-like domains, likely for cellular adhesion or interacting with the extracellular matrix. CDCP1 can be hydrolyzed by proteases like ADAM9, forming homodimers. This event induces tyrosine phosphorylation by proteins like Src and PKCδ, thereby initiating metastatic activity (Figure 1) ^[2-4].

1.2 CDCP1 Expression and Function

CDCP1 expression appears in vivo in various tissue stem cells and precursors, including hematopoietic stem cell progenitors and neural progenitor cells. Recent research links dysregulated CDCP1 expression to tumorigenesis, driving migration and invasion in malignancies, a vital role in tumor development. Furthermore, CDCP1's impact extends to tumor development through regulating intra-tumor cytokines. This role affects the tumor immune response by governing cytokine activity, including IL-2 and HLA-B19, ultimately impacting treatment outcomes. CDCP1 is now a prominent target in anti-tumor drug research ^[5-6].

Figure 1. CDCP1 structure ^[2]

2. How's the Mechanism Actions of CDCP1 in Tumors?

Currently, the mechanism of tyrosine phosphorylation interaction between SFKs, PKCδ and CDCP1 is receiving attention. Relevant studies have shown that CDCP1 interact with SFKs, PKCδ, and PKCδ by regulating downstream complex amino acid phosphorylation signaling pathways such as PI3K/Akt, PKC5, SRC and ERK/MAPK etc., play important roles in promoting tumor invasion and metastasis (Figure 2) ^[7].

In prostate cancer cells, CDCP1 gene expression is usually suppressed by androgens, maintaining low levels. Yet, androgen-independent prostate cancer sees elevated CDCP1 due to androgen deprivation. This activates Akt and SRC/MAPK pathways, possibly driving CRPC progression ^[8]. Additionally, CDCP1 deletion regulates CDK5, impacting integrin β1/ITGB1 expression in non-adherent cells and promoting vascular proliferation in advanced prostate cancer patients ^[9].

In colorectal cancer, CDCP1 boosts Wnt signaling via β-catenin and E-cadherin translocation ^[10]. In triple-negative breast cancer, PDGF-BB activates PDGFRβ, triggering ERK1/2 and raising CDCP1 expression ^[11]. In lung cancer, ADAM9 activates EGFR and decreases miR-1, upregulating CDCP1 and promoting progression ^[12]. Kidney cancer shows HIF-2α overexpression fueling CDCP1 and tyrosine phosphorylation, suggesting CDCP1 as a metastatic cancer biomarker and target ^[13].

Figure 2. CDCP1 associated signaling pathway in tumors ^[7]

3. The Role of CDCP1 in Various Tumors

3.1 CDCP1 and Prostate Cancer

Prostate Cancer (PCa) is a prevalent male tumor. Androgen Deprivation Therapy (ADT) effectively manages advanced prostate cancer and prevents recurrence by either suppressing androgen production or blocking Androgen Receptor (AR) signaling. Yet, drug resistance emerges in most patients, leading to androgen-independent and therapy-resistant Prostate Cancer (CRPC). Consequently, CRPC remains a formidable clinical challenge ^[14].

CDCP1 is highly expressed in AR-negative CRPC cells, correlating positively with BRD4 and CBP/p300. These are vital regulators upstream in the PCa cell pathway. Targeting them lowers oncogenic markers like EGFR, c-Myc, ERK/p-ERK、Akt/p-Akt and more. BRD4 and CBP/p300 bind CDCP1 gene regions, impacting H3K27ac levels and transcription. Dual inhibitor NEO2734 effectively curbs CDCP1 expression and hampers growth in AR-positive and AR-negative CRPC cells (Figure 3) ^[15]. Also, CDCP1, in synergy with PTEN deficiency, promotes metastatic prostate cancer development ^[16].

Figure 3. Targeting CDCP1 via dual inhibitor curbs CRPC development ^[15]

3.2 CDCP1 and Colorectal Cancer

CDCP1 is a molecular marker associated with the prognosis of colorectal cancer. Patients with its high expression have shorter overall and disease-free survival than those with low expression. In in vitro experiments, silencing the expression of CDCP1 could effectively inhibit the migration and invasion ability of HCT116 cells, suggesting that overexpression of CDCP1 promotes the metastasis and invasion of cancer cells. In addition, RHO-associated frizzled helix-binding protein kinase 1 (ROCK1) is an important downstream signaling molecule in the regulation of migration and invasion by CDCP1 ^[17].

3.3 CDCP1 and Lung Cancer

Lung cancer is one of the common malignant tumors, of which non-small cell lung cancer (NSCLC) accounts for more than 70-80% of lung cancers. For EGFR mutation-positive NSCLC patients treated with EGFR TKI, researchers found that CDCP1 is an independent negative prognostic factor affecting patients' Progression-Free Survival (PFS) and Overall Survival (OS) ^[18-19]. A related study found that high levels of ADAM9 and CDCP1 in clinical specimens of lung cancer patients were associated with high mortality. In addition, ADAM9 activates the EGFR signaling pathway and enhances CDCP1 expression to promote lung cancer ^{[12, 20]}.

3.4 CDCP1 and Pancreatic Cancer

In pancreatic cancer, CDCP1 shows high expression. AHCC, derived from mycorrhizal plants, can hinder pancreatic cancer's malignancy by lowering CDCP1 expression. Meanwhile, CDCP1's extracellular CUB2 domain allows it to form homotypic complexes by binding to another CDCP1 molecule. These complexes activate SFK signaling, propelling cancer cell migration. To counter this, researchers used a recombinant CUB2 domain protein (rMBPCUB2) tagged with maltose-binding protein, disrupting CDCP1 binding and reducing homotypic complexes. This hints that obstructing CDCP1's homotypic binding site could be a potential strategy for CDCP1-related tumor treatment ^[21].

3.5 CDCP1 and Breast Cancer

In breast cancer, CDCP1 is a key player in the HER2 signaling pathway, crucial for migration and tumor formation when both are overexpressed ^[22]. For triple-negative breast cancer (TNBC), FBXL14, a ubiquitin ligase, impacts CDCP1 levels. FBXL14 promotes CDCP1's ubiquitination and proteasomal degradation, curbing its stability. This, in turn, affects the expression of metastasis-related genes involving CDCP1 ^[23]. This study unveils a mechanism influencing CDCP1 stability, proving it a more accurate prognosis predictor in breast cancer than gene expression levels.

3.6 CDCP1 and Other Cancers

CDCP1 is also highly expressed in a variety of other cancers, such as laryngeal cancer ^[24], cervical cancer ^[25], renal cancer ^[13], hepatocellular carcinoma ^[26], chronic myeloid leukemia (CML) ^[27], and acute myeloid leukemia (AML) ^[28-29]. Taking laryngeal cancer as an example, a study detected MMP-9 in laryngeal cancer tissues and paracancerous tissues.They also examined MMP-9, CDCP1 and NLK levels in these tissues. Surprisingly, all three proteins were busier in the laryngeal cancer tissues, especially NLK. NLK acts a bit like a conductor for the cells' signals, directing their actions ^[24].

Besides, know-down of NLK expression in laryngeal cancer cells Hep-2 reduced the proliferation and invasion ability of cells and increased Caspase-3 activity. Caspase-3 is an apoptosis-related enzyme. Meanwhile, interfering with NLK expression also decreased the expression of MMP-9 and CDCP1. These results suggest that NLK may be involved in the proliferation, apoptosis, and invasion process of laryngeal cancer cells by affecting the expression of MMP-9 and CDCP1 ^[24].

4. The Clinical Potential of CDCP1 Targeted Therapy

Several global companies, like Chiome Bioscience, Inc., UCSF Innovation Ventures, Miltenyi Biotec, Inc., and Heidelberg Pharma Research GmbH, are investing in CDCP1 drug research. They're working on monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR T-cell therapies. Chiome Bioscience, Inc. stands out with its anti-CDCP1 antibody-drug conjugate (h14A043-ATAC), showing promise against solid cancers in preclinical stages. Their CDCP1 monoclonal antibody inhibitor (PCDC) is also in preclinical trials. All in all, these initiatives mark a significant leap towards realizing the potential of CDCP1-targeted therapies in various tumors.

In Conclusion:

CUB-domain containing protein 1 (CDCP1) is a cell surface glycoprotein, which is dysregulated in several cancers with potential as a target for cancer treatment. Backed by investments and collaborative research efforts from global leaders like Chiome Bioscience, Inc, CDCP1 presents a potential breakthrough against solid cancers in preclinical stages. More research is conducted to determine potent of targeting CDCP1 or associated proteins. Currently, CDCP1 is served as not only a marker for cancer, but also a cancer drug target!

5. CDCP1 Recombinant Proteins & Antibodies for Research Use

To fully support researchers and pharmaceutical companies in their research on CDCP1 in autoimmune diseases, tumors, or other diseases, CUSABIO presents CDCP1 active proteins & antibodies to support your research on the mechanism of CDCP1 or its potential clinical value.

CDCP1 protein

● Recombinant Human CUB domain-containing protein 1(CDCP1),partial (Active) (Code: CSB-MP884474HU)

High Purity Validated by SDS-PAGE

Purity was greater than 95% as determined by SDS-PAGE.

Excellent Bioactivity Validated by Functional ELISA

Immobilized Human CDCP1 at 2μg/mL can bind Anti-CDCP1 recombinant antibody (CSB-RA884474MA1HU), the EC₅₀ is 0.2943-0.4429 ng/mL.

● Recombinant Mouse CUB domain-containing protein 1(Cdcp1),partial (Active) (Code: CSB-MP719456MO)

High Purity Validated by SDS-PAGE

Purity was greater than 95% as determined by SDS-PAGE.

Excellent Bioactivity Validated by Functional ELISA

Immobilized Mouse Cdcp1 at 2 μg/mL can bind Anti-CDCP1 recombinant antibody (CSB-RA884474MA1HU), the EC₅₀ is 0.6397-0.8369 ng/mL.

● Recombinant Macaca fascicularis CUB domain containing protein 1(CDCP1),partial(Active) (Code: CSB-MP4569MOV)

High Purity Validated by SDS-PAGE

Purity was greater than 95% as determined by SDS-PAGE.

Excellent Bioactivity Validated by Functional ELISA

Immobilized Macaca fascicularis CDCP1 at 2μg/mL can bind Anti-CDCP1 recombinant antibody (CSB-RA884474MA1HU)，the EC₅₀ is 1.861-2.330 ng/mL.