ABSTRACT
The generation of drugs counteracting deregulated protein kinases has been a major focus in cancer therapy development. Breakthroughs in this effort have produced many therapeutic agents to the benefit of patients, mostly through the development of chemical or antibody-based drugs targeting active kinases. These strategies are challenged when considering catalytically inactive protein kinases (or pseudokinases), which represent 10% of the human kinome with many of relevance in cancer. Among the so-called pseudotyrosine kinases, the PTK7 receptor tyrosine kinase (RTK) stands as a bona fide target overexpressed in several solid tumors and hematological malignancies and linked to metastasis, poor prognosis, and resistance to treatment. Despite the lack of catalytic activity, PTK7 has signaling capacities through heterodimerization with active RTKs and offers pharmacological targeting opportunities through its inactive kinase domain. Moreover, PTK7-targeting strategies based on antibody-drug conjugates, aptamers, and CAR-T cell-based therapies have demonstrated encouraging results in preclinical and clinical settings. We review the most recent data assigning to PTK7 a prominent role in cancer progression as well as current preclinical and clinical targeting strategies against RTK family pseudokinases including PTK7.
Subject(s)
Cell Adhesion Molecules , Molecular Targeted Therapy , Neoplasms , Receptor Protein-Tyrosine Kinases , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Cell Adhesion Molecules/metabolism , Cell Adhesion Molecules/antagonists & inhibitors , Molecular Targeted Therapy/methods , Animals , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effectsABSTRACT
Prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate gland and is strongly upregulated in prostatic adenocarcinoma, with elevated expression correlating with metastasis, progression, and androgen independence. Because of its specificity, PSMA is a major target of prostate cancer therapy; however, detectable levels of PSMA are also found in other tissues, especially in salivary glands and kidney, generating bystander damage of these tissues. Antibody target therapy has been used with relative success in reducing tumor growth and prostate specific antigen (PSA) levels. However, since antibodies are highly stable in plasma, they have prolonged time in circulation and accumulate in organs with an affinity for antibodies such as bone marrow. For that reason, a second generation of PSMA targeted therapeutic agents has been developed. Small molecules and minibodies have had promising clinical trial results, but concerns about their specificity had arisen with side effects due to accumulation in salivary glands and kidneys. Herein we study the specificity of small molecules and minibodies that are currently being clinically tested. We observed a high affinity of these molecules for PSMA in prostate, kidney and salivary gland, suggesting that their effect is not prostate specific. The search for specific prostate target agents must continue so as to optimally treat patients with prostate cancer, while minimizing deleterious effects in other PSMA expressing tissues.
Subject(s)
Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/pathology , Antigens, Surface/metabolism , Prostate-Specific AntigenABSTRACT
Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/ß-catenin pathway signaling, in part, through a kinase domain-dependent interaction with the ß-catenin protein. PTK7 is overexpressed in CRC, an event associated with metastatic development and reduced survival of nonmetastatic patients. In addition, numerous alterations have been identified in CRC inducing constitutive activation of the Wnt/ß-catenin pathway signaling through ß-catenin accumulation. Thus, targeting the PTK7/ß-catenin interaction could be of interest for future drug development. We have developed a NanoBRET screening assay recapitulating the interaction between PTK7 and ß-catenin to identify compounds able to disrupt this protein-protein interaction. A high-throughput screening allowed us to identify small-molecule inhibitors targeting the Wnt pathway signaling and inducing antiproliferative and antitumor effects in vitro in CRC cells harboring ß-catenin or adenomatous polyposis coli (APC) mutations. Thus, inhibition of the PTK7/ß-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on the Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.
Subject(s)
Colorectal Neoplasms , Wnt Signaling Pathway , Cell Adhesion Molecules , Cell Proliferation , Colorectal Neoplasms/genetics , Humans , Mutation , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/pharmacology , Wnt Signaling Pathway/genetics , beta Catenin/metabolismSubject(s)
Cell Adhesion Molecules/antagonists & inhibitors , Medical Oncology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Adhesion Molecules/physiology , Drug Development/methods , Drug Development/trends , Humans , Medical Oncology/methods , Medical Oncology/trends , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/trends , Protein Kinase Inhibitors/isolation & purification , Receptor Protein-Tyrosine Kinases/physiologyABSTRACT
Triple negative breast cancers (TNBC) remain a major medical challenge due to poor prognosis and limited treatment options. Mesothelin is a glycosyl-phosphatidyl inositol-linked membrane protein with restricted normal expression and high level expression in a large proportion of TNBC, thus qualifying as an attractive target. Its overexpression in breast tumors has been recently correlated with a decreased disease-free survival and an increase of distant metastases. The objective of the study was to investigate the relevance of a bispecific antibody-based immunotherapy approach through mesothelin targeting and CD16 engagement using a Fab-like bispecific format (MesobsFab). Using two TNBC cell lines with different level of surface mesothelin and epithelial/mesenchymal phenotypes, we showed that, in vitro, MesobsFab promotes the recruitment and penetration of NK cells into tumor spheroids, induces potent dose-dependent cell-mediated cytotoxicity of mesothelin-positive tumor cells, cytokine secretion, and decreases cell invasiveness. MesobsFab was able to induce cytotoxicity in resting human peripheral blood mononuclear cells (PBMC), mainly through its NK cells-mediated antibody dependent cell cytotoxicity (ADCC) activity. In vivo, the anti-tumor effect of MesobsFab depends upon a threshold of MSLN density on target cells. Collectively our data support mesothelin as a relevant therapeutic target for the subset of TNBC that overexpresses mesothelin characterized by a low overall and disease-free survival as well as the potential of MesobsFab as antibody-based immunotherapeutics.
