Inactive protein tyrosine kinase 7 (PTK7), also known as colon cancer kinase 4 (CCK-4), is a component of both the non-canonical (also known as Wnt/planar cell polarity signaling) and canonical Wnt signaling pathways. It plays a role in cell adhesion, cell migration, cell polarity, proliferation, actin cytoskeleton reorganization, and apoptosis. It also plays a role in embryogenesis, epithelial tissue organization, and angiogenesis. PTK7 is highly expressed in both solid and hematologic tumors and is associated with metastasis, poor prognosis, and treatment resistance.

PTK7 expression distribution

PTK7 is primarily expressed in late spermatids, early spermatids, and endometrial stromal cells. PTK7 expression is relatively low in adult tissues but highly expressed in cancer cells, such as colon cancer, lung cancer, breast cancer, and cervical cancer.

(Data source: Uniprot)

Structure of PTK7

PTK7 is a single-pass transmembrane protein. The PTK7 protein consists of an extracellular domain containing seven immunoglobulin (Ig)-like loops, a transmembrane region, and an intracellular kinase domain, and is subject to alternative splicing events, resulting in the expression of different isoforms. MT1-MMP is the major sheddase of PTK7, which directly cleaves the exposed PKP (621) ↓ LI sequence to produce an N-terminal soluble PTK7 fragment (sPTK7). Although the pseudokinase domain of PTK7 lacks catalytic activity, its αC helix is in an "in" conformation, allowing the formation of an αC/β3 salt bridge, which is a characteristic of active kinases. The PTK7 kinase domain has no ability to bind ATP and Mg²⁺.

(Data source: Dessaux C, et al. Oncogene. 2024)

Signaling pathway regulation by PTK7

WNT/PCP pathway: PTK7, a positive regulator of planar cell polarity (PCP), interacts with ROR2 and the non-canonical WNT ligand WNT5a to promote cytoskeletal reorganization and cell motility. This interaction plays a key role in embryonic development and cancer invasion.

Role of PTK7 in the WNT/β-catenin pathway: PTK7 directly interacts with β-catenin and promotes downstream events induced by WNT3a ligands.

Role of PTK7 in WNT-independent signaling pathways: PTK7 expression is elevated in human vascular endothelial cells. PTK7 interacts with the RTK FLT-1/VEGFR1, promoting its phosphorylation, AKT activity, and VEGF-induced cell migration and angiogenesis. PTK7 also activates angiogenesis by regulating KDR/VEGFR2, particularly its oligomerization.

Proteolytic Cleavage and Nuclear Translocation: The signaling function of PTK7 is regulated by proteolytic cleavage events. Metalloproteinases such as MT1-MMP and ADAM17 cleave PTK7, leading to the release of soluble PTK7 (sPTK7) and nuclear translocation of the intracellular domain (ICD). This cleavage and translocation may modulate PTK7 signaling output, affecting cell migration and proliferation.

(Data source: Dessaux C, et al. Oncogene. 2024)

Targeted therapy of PTK7

Overexpression of PTK7 in solid and hematological tumors is strongly associated with poor prognosis and treatment resistance, suggesting that this receptor may represent a valuable biomarker and/or therapeutic target. Targeting pseudokinases remains a challenge in therapeutic development. The lack of enzymatic activity and its context-dependent roles within the plasma membrane and nucleus have limited the development of drugs that antagonize PTK7 function. Most established strategies are designed to enhance its expression in tumors, using antibody-drug conjugates. These strategies are supplemented by CAR-T cell immunotherapy and small molecule inhibitors targeting PTK7. Currently, only a few drugs have entered clinical development, with the majority still in preclinical studies.

(Data source: Dessaux C, et al. Oncogene. 2024)

PF-06647020/cofetuzumab pelidotin is an antibody-drug conjugate targeting PTK7. Preclinical studies have demonstrated sustained tumor regression in patient-derived TNBC, NSCLC, and OVCA xenograft models, with antitumor activity exceeding standard chemotherapy and a reduction in the frequency of tumor-initiating cells (TICs). A first-in-human Phase 1 study of PF-06647020 in patients with advanced solid tumors refractory to or refractory to standard therapy has subsequently been completed. This study demonstrated a tolerable safety profile and preliminary clinical activity of this ADC in patients with PTK7-positive solid tumors. Further clinical studies are underway to evaluate its therapeutic potential. Another Phase 1 study (NCT03243331) combining PF-06647020 with a PI3K/mTOR signaling inhibitor for the treatment of metastatic TNBC is underway, but results are not yet available.

PRO-1107 is an antibody-drug conjugate targeting PTK7 developed by ProfoundBio for the treatment of advanced malignant solid tumors, endometrial cancer, gastroesophageal junction malignancies, non-small cell lung cancer, ovarian epithelial cancer, urothelial cancer, and triple-negative breast cancer.

Solid tumors and other diseases. A global, open-label, multicenter Phase 1/2 study (NCT06171789) is currently underway to evaluate the safety and tolerability, pharmacokinetics (PK), and anti-tumor activity of PRO1107 in patients with advanced solid tumors.

(Data source: Jin Z, et al. Front Oncol. 2024)