Therapeutic advances of targeting receptor tyrosine kinases in cancer

Abstract

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Fig. 1

Structure of the 20 Receptor Tyrosine Kinase Classes. The RTKs structure differs from one receptor to another, with several similarities and differences mostly at the extracellular and intracytoplasmic domains as depicted from left to right in all 20 RTKs classes. Images created with BioRender.com

Fig. 2

Activation and Intracellular Signaling Mechanisms of Receptor Tyrosine Kinase. Depicted from left to right, the Ligands are binding to the monomer RTKs and trigger the dimerization with a cross-phosphorylation of the protein kinase domains. Further secondary transphosphorylation of the tyrosine kinase domains, juxtamembrane and c-terminal regions occur in the RTKs, which will further create the proper conditions for the recruitment of the intracellular substrates that will further lead to the activation of the key proteins in the downstream signaling pathways. Images created with BioRender.com

Fig. 3

Termination of RTKs signaling—endocytosis of signaling and Endocytic Trafficking. The red arrows in the figure illustrate variations in the endocytic rate and pathway selection, which are determinant factors for the modulation of RTK surface expression and downstream signaling, potentially driving oncogenic processes. Images created with BioRender.com

Fig. 4

RTKs dysregulation mechanisms. The dysregulation of RTKs may occur by a gain-of -function mutation, an amplification, chromosomal rearrangements, TK domain duplication or by an autocrine or paracrine activation (left to right). The dysregulations are generating abnormal activation of the RTKs which will be translated into enhanced proliferation, differentiation or angiogenesis, same as into a dysregulated cell cycle and metabolism. Images created with BioRender.com

Fig. 5

Outline of RTK families—downstream effectors—RTK inhibitors. The RTK downstream signaling is linked to several key biological pathways such as Rac/MEKK/JNK, Ras/Raf/MEK/ERK, PI3K/Akt/mTOR and NF-kB, JAK/STAT or Rho and calcium signaling, modulating gene expression and cellular metabolism. The biological processes that are influenced by the RTKs status are related to cell survival, migration, differentiation, growth, proliferation, and angiogenesis. Images created with BioRender.com

Fig. 6

Main resistance mechanisms to RTK inhibitors. The hypoxic tumor cells that express HIF have overstimulated proangiogenic status and promote tumor vascularization and resistance to RTK inhibitors (left). The secreted exosomes containing genetic information (RNAs, long noncoding RNAs) stimulate epithelial to mesenchymal transition disturbing cell adhesion and increasing motility and invasiveness. The stimuli from the hypoxic cells influence other cells behavior by inducing RTKs reorganization, changes in their conformation and protein degradation. Oxidative stress (as an external stimuli) disrupts the mitochondrial metabolic pathways changing the balance within the cells leading to drug resistance. Drug uptake and transport are affected by the changes induced in the carriers and membrane transporters which may disrupt the drug uptake leading to an increased resistance to RTK inhibitors by externalizing the drugs via active mechanisms. The low-right box depicts the resistance to therapy induced by genetic mutations by epigenetic changes that induce mutation in the genes encoding the RTK proteins or other downstream proteins involved in key biological processes such as survival, proliferation or programed cell death. Images created with BioRender.com