Tyrosine Kinase Receptors in Oncology.

Jorge Esteban-Villarrubia,Juan José Soto-Castillo,María San Román-Gil,Javier Molina-Cerrillo,Javier Pozas,Javier Torres-Jiménez,Teresa Alonso-Gordoa,Inmaculada Orejana-Martín,Alfredo Carrato

doi:10.3390/ijms21228529

Abstract

Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

Highlights

Since the discovery of tyrosine kinase receptors (TKR) in the 60 s, and their subsequent classification by families, it has been revealed how the function of these receptors is key in different aspects of the cell biology
The aim of this review is to provide a comprehensive insight of the different roles of the TKRs within the cell biology, how their alteration can lead a tumorigenesis process and which drugs are currently available or under development to stop tumor progression
We can distinguish between basket and umbrella trials: In the former, patients are selected based on the same molecular alteration in spite of the tumor origin, whilst in the latter, they are selected based on the same tumor type or location and subdivided depending on the molecular alteration identified

Summary

Introduction

Since the discovery of tyrosine kinase receptors (TKR) in the 60 s, and their subsequent classification by families, it has been revealed how the function of these receptors is key in different aspects of the cell biology In the meantime, it has been discovered how the alterations in the normal function of these receptors can play a key role in the development of tumors, from early stages of the disease to more advanced ones. Most of the receptors are activated by a process called transphosphorylation, while others are activated by conformational changes caused by the interaction of the tyrosine kinase domains Both processes conclude in the phosphorylation of some tyrosine residues in the cytosolic side of the protein, which are the docking sites for some intracellular signalling proteins. These proteins bind to a specific site of the receptor by the reckoning of phosphotyrosine residues by a docking domain, which is usually the Src homologue 2 (SH2) or phosphotyrosine binding (PTB) type

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