Targeting Wnt signaling pseudokinases in hematological cancers

Abstract

Recent studies showed that several pseudokinases from the receptor tyrosine kinase family are important players in regulating cancer cell invasion, metastasis, and drug resistance, suggesting that targeting these proteins can play a therapeutic role in cancer treatment. Receptor Tyr kinase-like orphan receptors (RORs), protein Tyr kinase 7 (PTK7) (also called colon carcinoma kinase 4 (CCK4)), and receptor-like Tyr kinase (RYK) are Wnt ligand binding receptors within the non-canonical Wnt signaling, with important roles in development, tissue homeostasis, and organogenesis. At the cellular level, these receptors transduce signals important for cell survival, migration, polarization, and chemotaxis. Considerable progress has been made in the last decade in the field of pseudokinase signaling, improving our understanding of their structure-function mechanisms, and intracellular network of transduction components. Consequently, their role in various diseases, including cancer, is now scrutinized for therapeutic interventions to improve treatment outcome. In this article, we review findings regarding molecular mechanisms and targeted therapies for ROR1, PTK7, and RYK in hematological malignancies.

Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways

“…In similar studies for hematological cancers, the combination of cirmtuzumab and ibrutinib was more efficient in eradicating leukemic cells in vivo [74], whereas the ex vivo co-targeting of ROR1 and Bcl-2 in CLL, MCL or B-ALL patient samples was significantly more effective than targeting a single pathway, strongly supporting the implementation of these combinatorial regimens in clinical trials [13,39,40]. Apart from cirmtuzumab, other ROR1 monoclonal antibodies have been developed and tested at preclinical levels [75]. A potent immunotherapeutic approach was used to develop bispecific antibodies (biAbs) that combine a T cell-engaging arm with a tumor cell-binding arm, for which ROR1 seemed a perfect candidate due to its relatively restricted expression on tumor cells.…”

PTK7-Targeting CAR T-cells for the Treatment of Lung Cancer and other Malignancies

“…In fact, CAR T cells targeting several biomarkers of TICs/CSCs, including CD133, CD24, Receptor tyrosine kinase-like orphan receptor 1 (ROR1) or the epithelial cell adhesion molecule (EpCAM) have been developed and exhibited the excellent antitumor effects in preclinical models [34][35][36][37][38][39][40]; more importantly, CD133-targeting CAR T cells alone or in combination have demonstrated antitumor activity in treating patients with CD133-postive metastasis malignancies with controllable toxicities in clinical trials [41,42]. Intriguingly, both PTK7 and ROR1 belong to Wnt ligand binding receptors with important roles in the non-canonical Wnt signaling [10]. ROR1 exhibits high and homogeneous cell surface expression in many epithelial tumors with expression pro le similar to PTK7, and targeting ROR1 with CAR T-cell therapy improved survival in xenograft models of ROR1 + human tumors with treating lung and breast cancer in an ongoing clinical trial (NCT02706392) [38,40].…”

“…Cautions still should be taken when translating this PTK7-CAR T cells into clinic considering different mechanisms of action and target recognition sensitivity between ADC and CAR T cells directing the same targets. In addition, we may learn from the experience of targeting ROR1 by CAR T cells as these two molecules have the similar expression pro le in both normal and tumor tissues [10,49]. Although ROR1-CAR T cells (derived from R12-and 2A-scFv) without cross reactivity with murine ROR1 exhibited no evident toxicity in NSG mice tumor model, murine ROR1-speci c CAR T cells (derived from R11-scFv) induced lethal bone marrow failure due to recognition of ROR1 + stromal cells which can be rescued by the logic-Gated strategy of CAR construction [38,40].…”

“…PTK7, also known as colon carcinoma kinase 4 (CCK-4), is a member of the pseudokinase family of receptor tyrosine kinases (RTKs) that has an intracellular catalytically inactive tyrosine kinase-like domain [10,11]. PTK7 is expressed during embryogenesis but absent from normal vital adult tissues, apart from a subset of immature CD4+ recent thymic emigrants (RTEs) and plasmacytoid dendritic cells (pDCs), and low level expression on some normal tissues [10][11][12]. Genetic and biochemical studies have demonstrated an involvement of PTK7 in noncanonical Wnt signaling via interacting with Wnt ligands such as ROR2, Wnt5a or Wnt3a [13,14].…”

“…In addition, evidence is also present for context-dependent roles of PTK7 in the vascular endothelial growth factor (VEGF), semaphorin/plexin, and canonical Wnt signaling pathways [11]. Oncogenic functions of PTK7 have been documented in several hematological and solid tumors [10,11]. Recent studies showed that PTK7 is overexpressed in triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), ovarian cancer (OVCA), cervical cancer, esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC) and enriched in tumor-initiating cells (TICs) from TNBC, OVCA, and NSCLC patientderived xenografts (PDXs), and its overexpression is associated with poor survival in NSCLC, cervical cancer, ESCC and HCC [12,[17][18][19][20][21][22].…”