Abstract
Simple SummaryTargeting oncogenic protein tyrosine phosphatases (PTPs) with specific pharmacological approaches has been considered for a long time a hard challenge, earning these PTPs the reputation of “undruggable” enzymes. Nevertheless, PTPs have been recognized as main targets for several diseases, including cancer, and great efforts have been made to identify novel PTPs inhibitors to fight cancer progression and metastasis formation. Here, we summarize recent evidence underlining the efficacy of this strategy for melanoma treatment. In particular, we illustrate how this approach could be applied to target both cancer cells and the immune infiltrate of tumors, providing a new promising adjuvant therapy for the treatment of melanoma.Despite a large number of therapeutic options available, malignant melanoma remains a highly fatal disease, especially in its metastatic forms. The oncogenic role of protein tyrosine phosphatases (PTPs) is becoming increasingly clear, paving the way for novel antitumor treatments based on their inhibition. In this review, we present the oncogenic PTPs contributing to melanoma progression and we provide, where available, a description of new inhibitory strategies designed against these enzymes and possibly useful in melanoma treatment. Considering the relevance of the immune infiltrate in supporting melanoma progression, we also focus on the role of PTPs in modulating immune cell activity, identifying interesting therapeutic options that may support the currently applied immunomodulating approaches. Collectively, this information highlights the value of going further in the development of new strategies targeting oncogenic PTPs to improve the efficacy of melanoma treatment.
Highlights
Reversible tyrosine phosphorylation is one of the most important post-translational modifications, which regulates key aspects of cellular biology, such as protein stability, protein–protein interactions, and enzyme activity [1], thereby modulating the functionality of fundamental elements involved in signaling transduction of mammalian cells [2]
The intracellular tyrosine phosphorylation level is maintained by a strict balance between the activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), which catalyze respectively the addition or the removal of phosphate from tyrosyl residues of their substrates [3]
These findings suggest that therapeutic strategies based on the treatment with Mitogen-Activated Protein Kinase Phosphatase-1 (MKP1) inhibitors could contribute to improve the prognosis of patients affected by tumors expressing high MKP1 levels, such as melanoma
Summary
Reversible tyrosine phosphorylation is one of the most important post-translational modifications, which regulates key aspects of cellular biology, such as protein stability, protein–protein interactions, and enzyme activity [1], thereby modulating the functionality of fundamental elements involved in signaling transduction of mammalian cells [2]. The loss of function of PTEN is observed in about 10–35% of cutaneous melanomas, where it confers resistance to BRAF inhibitors This mutation results in a constitutive activation of the PI3K/AKT pathways, which, in turn, leads to cell growth and proliferation and to the inhibition of apoptosis [50]. This approach could provide longer lasting therapeutic benefits through the inhibition of multiple nodes in the main oncogenic signaling pathways In agreement with this hypothesis, Prahallad and co-authors found that the suppression of Src homology region 2 domain-containing phosphatase-2 (SHP-2) in BRAF mutant and in Vemurafenib-sensitive melanoma cells inhibits growth factor-induced drug resistance and delays the onset of spontaneous resistance [56]. This information lays the foundation for the design of new therapeutic strategies directed against oncogenic PTPs in melanoma [61]
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