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

Hanna Karvonen,Laura Kaleva,Wilhelmiina Niininen,Daniela Ungureanu,Harlan Barker

doi:10.3390/cells8080812

Abstract

Signaling via the Wnt-related receptor tyrosine kinase-like orphan receptor 1 (ROR1) triggers tumorigenic features associated with cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT), while aberrant expression of ROR1 is strongly linked to advanced disease progression and chemoresistance. Several recent studies have shown that Wnt5a binding to ROR1 promotes oncogenic signaling by activating multiple pathways such as RhoA/Rac1 GTPases and PI3K/AKT, which in turn could induce transcriptional coactivator YAP/TAZ or polycomb complex protein BMI-1 signaling, respectively, to sustain stemness, metastasis and ultimately drug-resistance. These data point towards a new feedback loop during cancer development, linking Wnt5a-ROR1 signaling activation to YAP/TAZ or BMI-1 upregulation that could play an important role in disease progression and treatment resistance. This review focuses on the crosstalk between Wnt5a-ROR1 and YAP/TAZ or the BMI-1 signaling network, together with the current advancements in targeted strategies for ROR1-positive cancers.

Highlights

The Wnt pathway plays essential roles in development, tissue homeostasis and disease, by transducing signals from 19 Wnt ligands via a complex network of receptors and co-receptors [1] that can be classified into canonical (β-catenin dependent) and non-canonical (β-catenin independent)Wnt signaling
There is a considerable overlap among Wnt ligands and their specific receptors when it comes to their involvement in canonical or non-canonical Wnt signaling, it is accepted that the canonical Wnt pathway primarily regulates cell proliferation and differentiation, while non-canonical Wnt signaling regulates cell polarity, adhesion, and motility [2]
Four Wnt binding receptors belong to the receptor tyrosine kinases as well as the pseudokinase family and are mediators of non-canonical Wnt signaling; these are receptor tyrosine kinase-like orphan receptor 1/2 (ROR1/ROR2), protein tyrosine kinase 7/colon carcinoma kinase 4 (PTK7/CCK4), and tyrosine protein kinase (RYK)

Summary

Introduction

The Wnt pathway plays essential roles in development, tissue homeostasis and disease, by transducing signals from 19 Wnt ligands via a complex network of receptors and co-receptors [1] that can be classified into canonical (β-catenin dependent) and non-canonical (β-catenin independent). Recent studies have shown that acquired resistance to T-DM1 (trastuzumab emtansine, a newly developed antibody-drug conjugate) in HER2+ breast cancer patients induced high ROR1 expression on neoplastic cells that exhibit stem cell signatures (such as expression of both CD44 and ALDH1), resulting in an enhanced capacity to form spheroids and self-renewal properties [21] In another disease model, resistance to the MEK inhibitor trametinib in uveal melanoma was associated with the upregulation of ROR1 and YAP/TAZ signaling, resulting in treatment resistance in preclinical models.

Crosstalk between in Tumorigenesis

Progress in ROR1-Targeted Therapies