Recent insights into the therapeutic strategies targeting the pseudokinase PTK7 in cancer

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.