Targeting Phosphatases and Kinases: How to Checkmate Cancer

Abstract

Metastatic disease represents the major cause of death in oncologic patients worldwide. Accumulating evidence have highlighted the relevance of a small population of cancer cells, named cancer stem cells (CSCs), in the resistance to therapies, as well as cancer recurrence and metastasis. Standard anti-cancer treatments are not always conclusively curative, posing an urgent need to discover new targets for an effective therapy. Kinases and phosphatases are implicated in many cellular processes, such as proliferation, differentiation and oncogenic transformation. These proteins are crucial regulators of intracellular signaling pathways mediating multiple cellular activities. Therefore, alterations in kinases and phosphatases functionality is a hallmark of cancer. Notwithstanding the role of kinases and phosphatases in cancer has been widely investigated, their aberrant activation in the compartment of CSCs is nowadays being explored as new potential Achille’s heel to strike. Here, we provide a comprehensive overview of the major protein kinases and phosphatases pathways by which CSCs can evade normal physiological constraints on survival, growth, and invasion. Moreover, we discuss the potential of inhibitors of these proteins in counteracting CSCs expansion during cancer development and progression.

Discovery of Novel Small-Molecule Scaffolds for the Inhibition and Activation of WIP1 Phosphatase from a RapidFire Mass Spectrometry High-Throughput Screen

“…71 Therefore, kinases and phosphatases have long been considered as therapeutic targets, especially in cancer. 72,73 While drug development for kinase modulation has been immensely successful in the past 20 years, particularly in the field of oncology, 74 it has been more challenging to target phosphatases. However, these enzymes, once considered undruggable, are more frequently pursued in drug development.…”

Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A

“…WNK1 can regulate many oncogenic pathways, including the WNT/β-catenin and TGF-β-SMAD2 pathways, and it can increase the nuclear levels of the EMT-related transcription factors SLUG and FOXO1 [ 49 ]. Detailed discussion of the oncogenic potential of other kinases that were phosphorylated by BPA can be found elsewhere [ 7 , 50 , 51 ].…”

Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

“…PTPs are difficult to target specifically using small molecule inhibitors. In this regard, the diversity of regulatory and protein interaction domains present in PTPs offers a wide variety of potential intervention points in addition to direct modulation of catalysis by compounds targeting the enzyme active site ( Stanford and Bottini, 2017 ; Turdo et al, 2021 ). Since dual pro- and anti-oncogenic properties are proposed for several PTPs in neuroblastoma, dedicated studies are necessary that address the expression, subcellular location, and substrate specificity of individual PTPs in different neuroblastoma scenarios.…”