AKT kinases as therapeutic targets

Autor: Dalal Hassan, Craig W. Menges, Joseph R. Testa, Alfonso Bellacosa
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Journal of Experimental & Clinical Cancer Research, Vol 43, Iss 1, Pp 1-37 (2024)
Druh dokumentu: article
ISSN: 1756-9966
50794523
DOI: 10.1186/s13046-024-03207-4
Popis: Abstract AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.
Databáze: Directory of Open Access Journals
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