PTK7: Exploring a Promising Target for Cancer Therapeutics

Protein tyrosine kinase 7 (PTK7) is an evolutionarily conserved transmembrane receptor belonging to the receptor tyrosine kinase (RTK) family, and it is also a distinct class of tyrosine kinase protein lacking kinase activity. PTK7 was initially discovered due to its upregulated gene expression in colon cancer cells, hence it is also known as colon carcinoma kinase 4 (CCK-4). Subsequent studies revealed that PTK7 also plays a crucial role in various other cancers, such as lung, breast, gastric, and esophageal cancers. PTK7 has now emerged as a potential target for cancer therapy.

Structure and Function of PTK7

The PTK7 gene is located on the short arm of human chromosome 6 (6p21.1). Its protein structure consists of three components: an extracellular region featuring 7 immunoglobulin (Ig)-like domains, a transmembrane domain, and a receptor tyrosine kinase family homologous domain lacking catalytic activity. Due to this lack of catalytic activity, PTK7 is classified as a pseudokinase and is unable to bind ATP and Mg²⁺ Membrane-type 1 matrix metalloproteinase (MT1-MMP) serves as the primary sheddase for PTK7; it can directly cleave the exposed PKP(621)↓LI sequence on PTK7, producing a soluble PTK7 N-terminal fragment (sPTK7).

Schematic Diagram of PTK7 Protein Structure^[1]

Studies related to colon cancer demonstrate that PTK7 is first cleaved by ADAM17, generating a soluble fragment containing the 7 Ig-like domains (sPTK7-Ig1-7) and C-terminal fragment 1 (PTK7-CTF1). The generated PTK7-CTF1 is further cleaved by γ-secretase into PTK7 C-terminal fragment 2 (PTK7-CTF2). After translocating to the nucleus, PTK7-CTF2 promotes the proliferation and migration of SW480 colon cancer cells.  

Intracellular Domains Generated by PTK7 Cleavage Promote Colon Cancer Development^[1]

As a co-receptor of the Wnt signaling pathway, PTK7 is involved in regulating physiological processes such as cell proliferation, cell migration, the establishment of planar cell polarity, and differentiation under normal conditions, playing a critical role in tissue morphogenesis and tissue patterning. Conversely, PTK7 expression is dysregulated across multiple cancers. Research indicates that in low-passage patient-derived xenograft (PDX) models of triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer, PTK7 is abundantly expressed on tumor-initiating cells (TICs), promotes tumor growth and invasion, and participates in mediating tumor therapeutic resistance, with its activity level directly correlating to poor cancer prognosis^[2][3].

Different Roles of PTK7 in Physiological Conditions and Cancer Progression^[3]

PTK7-Mediated Signaling Pathways

The Wnt signaling pathway is a vital mediating pathway through which PTK7 regulates organismal functions; PTK7 can interact with various Wnt receptors, thereby influencing both canonical and non-canonical Wnt signaling pathways. The exact role of PTK7 within the canonical Wnt signaling pathway remains controversial; some studies confirm that it activates this pathway, while others indicate it exerts an inhibitory effect. Additionally, PTK7 is involved in regulating the planar cell polarity (PCP) pathway, which determines the orientation of cells within an epithelial plane, a process reflecting PTK7's role in the non-canonical Wnt signaling pathway. PTK7's role as a molecular signaling switch is not limited to the Wnt pathway; it can also act as a molecular switch for the vascular endothelial growth factor (VEGF) signaling pathway and can form a receptor complex with Flt-1 (VEGFR1), playing a key role in Flt-1-mediated angiogenesis^[1]. 

PTK7-Mediated Canonical/Non-Canonical Wnt Signaling Pathways^[4]

Non-canonical Wnt/Planar Cell Polarity (PCP) Pathway

Non-canonical PCP signaling is activated by ligands such as Wnt5a and Wnt11. This signal is transduced via Frizzled receptors and Dishevelled (Dsh) proteins, activating the GTPases RhoA and Rac, as well as their respective effector molecules Rho-associated kinase (Rock) and c-Jun N-terminal kinase (JNK). In the presence of Frizzled, PTK7 can bind to Dsh and participate in the activation of the Wnt/PCP pathway; the abnormal activation of this pathway plays a significant role in driving cancer progression, invasive metastasis, and angiogenesis. 

Canonical Wnt Pathway 

In the absence of Wnt ligands, cytoplasmic β-catenin binds with adenomatous polyposis coli (APC) protein, Axin-1, and glycogen synthase kinase 3β (GSK3β) to form a "destruction complex," which continuously phosphorylates β-catenin, leading to its degradation via a ubiquitin-mediated pathway. Because β-catenin levels are kept low, it cannot enter the nucleus, and the canonical Wnt pathway remains in an "off" state. Upon stimulation by the Wnt3a ligand, this complex disintegrates in a Dsh-dependent manner. PTK7 can stabilize β-catenin at the membrane, allowing it to accumulate and translocate to the nucleus, where it binds with lymphoid enhancer-binding factor/T-cell factor (LEF/TCF) transcription factors to activate the expression of target genes, thereby exerting a positive regulatory effect. Whether PTK7 similarly interacts with Dsh in the canonical Wnt pathway, and whether it binds with other receptors, still requires further investigation. However, the role of PTK7 in the canonical Wnt pathway is heavily debated; functional experiments conducted by other researchers in Xenopus, Drosophila, and mammalian cells have demonstrated that PTK7 inhibits the canonical Wnt signaling pathway, which completely contradicts the aforementioned conclusions^[5]. 

PTK7 Drug Development Progress

Because PTK7 lacks catalytic activity, it is difficult to follow the conventional strategies used for receptor tyrosine kinases to develop small molecule inhibitors. As a result, the primary drug modality is ADCs. Following the clinical failures of Cofetuzumab Pelidotin and PRO1107, the current PTK7 targeted drug market has formed a competitive landscape with Kelun-Biotech leading the way, while various domestic and international pharmaceutical companies accelerate to break through. SKB-518, developed by Kelun-Biotech based on its OptiDC™ platform, has reached phase II as its highest clinical progression and is intended for the treatment of non-small cell lung cancer and small cell lung cancer. The IND application for this drug targeting advanced solid tumor indications has been approved by the FDA and CDE, and it is currently in phase I clinical trials. MTX-13 is being jointly developed by MabCare and ProfoundBio; in June 2024, Day One announced an exclusive licensing agreement with MabCare for MTX-13, granting Day One exclusive global development, manufacturing, and commercialization rights outside of Greater China, and the drug is currently in phase I clinical trials. MTX-13 consists of an anti-PTK7 monoclonal antibody (Ab13) conjugated via a self-cleaving linker T1000 to 8 molecules of exatecan (a topoisomerase I inhibitor). In cell line-derived and patient-derived xenograft models of multiple solid tumors, MTX-13 demonstrated potent anti-tumor activity, with significantly superior efficacy compared to Cofetuzumab Pelidotin. In squamous cell carcinomas originating from different anatomical sites, MTX-13 exhibited potent anti-tumor activity. In rhesus monkeys, MTX-13 showed favorable pharmacokinetics and safety, with its highest non-severely toxic dose (HNSTD) ≥30 mg/kg, far exceeding the 3–5 mg/kg of Cofetuzumab Pelidotin. 

Structure and Pharmacological Advantages of MTX-13^[6] 

In addition to the above ADCs targeting a single PTK7 epitope, Zymeworks is developing a biparatopic ADC drug targeting two distinct PTK7 epitopes, specifically the Ig4 and Ig3-4 epitopes in the extracellular domain of PTK7; the two epitopes do not overlap, and the drug is currently in the preclinical stage. At the 2025 AACR Annual Meeting, Zymeworks disclosed relevant data showing that adopting a PTK7 biparatopic targeting strategy can significantly enhance antibody binding affinity and receptor-mediated endocytosis efficiency, achieving more efficient delivery of cytotoxic payloads to tumor cells. The drug demonstrated anti-tumor activity in both breast and lung cancer models, indicating a potential efficacy improvement over Cofetuzumab Pelidotin; furthermore, in non-human primate models, the drug still exhibited excellent safety and tolerability at a dose of 60 mg/kg. 

Recognition Sites of the Biparatopic PTK7 ADC Drug^[7]

A selection of PTK7 targeted drugs

KACTUS Supplies High-Quality PTK7 Proteins

As a key regulatory molecule in the Wnt signaling pathway, PTK7 has become a promising target in the field of ADC drug development, owing to its high expression characteristics in various solid tumors and its close association with tumor invasion and metastasis. Despite clinical setbacks for drug candidates like Cofetuzumab Pelidotin, the immense potential of PTK7-targeted therapies continues to attract domestic and international pharmaceutical companies to accelerate their positioning. KACTUS supplies high-quality wild-type PTK7 proteins, mutants, and PTK7 domain proteins, covering multiple species and featuring various tag designs. These products have undergone strict quality control and are suitable for diverse application scenarios such as immunization, screening, and epitope identification, fully supporting the development of PTK7-targeted drugs. 

Product Data

Immobilized Human PTK7, His Tag at 0.5 μg/ml (100μl/well) on the plate. Dose response curve for Anti-PTK7 Antibody, hFc Tag with the EC50 of 2.0 ng/ml determined by ELISA (QC Test).

Immobilized Cynomolgus PTK7, His Tag at 0.5 μg/ml (100μl/well) on the plate. Dose response curve for Anti-PTK7 Antibody, hFc Tag with the EC50 of 3.3ng/ml determined by ELISA. (QC Test)

Related Product

Catalog Number	Product Name
CCK-HM104	Human PTK7/CCK4, His Tag
CCK-HM104-UL	Human PTK7/CCK4 Protein, Ultra Low Endotoxin
CCK-HM204	Human PTK7/CCK4, hFc (IgG1) Tag
CCK-HM204-UL	Human PTK7/CCK4, Ultra Low Endotoxin, hFc (IgG1) Tag
CCK-HM404B	Biotinylated Human PTK7/CCK4, His-Avi Tag
CCK-HM114	Human PTK7/CCK4 (V354M) , His Tag
CCK-MM104	Mouse PTK7/CCK4, His Tag
CCK-MM404B	Biotinylated Mouse PTK7/CCK4 , His-Avi Tag
CCK-CM104	Cynomolgus PTK7/CCK4, His Tag
CCK-CM104-UL	Cynomolgus PTK7/CCK4, Ultra Low Endotoxin, His Tag
CCK-CM404B	Biotinylated Cynomolgus PTK7/CCK4, His-Avi Tag
CCK-RM104	Rat PTK7/CCK4, His Tag

References

[1] Jin Z, Guo T, Zhang X, Wang X, Liu Y. PTK7: an underestimated contributor to human cancer. Front Oncol. 2024 Oct 15;14:1448695. doi: 10.3389/fonc.2024.1448695. PMID: 39474113; PMCID: PMC11518688.
[2] Marc Damelin et al.A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.Sci. Transl. Med.9,eaag2611(2017).DOI:10.1126/scitranslmed.aag2611
[3] Mottard K, Cokaiko J, Rogister B, Neirinckx V. Therapeutic targeting of the protein tyrosine kinase-7 in cancer: an overview. Oncologist. 2025 Aug 4;30(8):oyae290. doi: 10.1093/oncolo/oyae290. PMID: 39468753; PMCID: PMC12395136.
[4] Lhoumeau AC, Puppo F, Prébet T, Kodjabachian L, Borg JP. PTK7: a cell polarity receptor with multiple facets. Cell Cycle. 2011 Apr 15;10(8):1233-6. doi: 10.4161/cc.10.8.15368. Epub 2011 Apr 15. PMID: 21415598.
[5] Peradziryi H, Tolwinski NS, Borchers A. The many roles of PTK7: a versatile regulator of cell-cell communication. Arch Biochem Biophys. 2012 Aug 1;524(1):71-6. doi: 10.1016/j.abb.2011.12.019. Epub 2012 Jan 3. PMID: 22230326.
[6] Kong C, Pu J, Zhao Q, Weng W, Ma L, Qian Y, Hu W, Meng X, Meng T. MTX-13, a Novel PTK7-Directed Antibody-Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors. Mol Cancer Ther. 2023 Oct 2;22(10):1128-1143. doi: 10.1158/1535-7163.MCT-23-0164. PMID: 37352387; PMCID: PMC10544008.
[7] PTK7-BiP-ADC-2025-AACR-Poster_Final_April-14-1.pdf