Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

Abstract

Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15-20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…AKT is regulated by a variety of hormones, including insulin and growth factors [26]. As mentioned above, after the PI3K regulatory subunit binds to the corresponding receptors or receptor-binding protein on the cell membrane, its catalytic subunit is activated and catalyses the formation of PIP3, which then recruits PDK1 and AKT to the cell membrane [26,27].…”

New Insights into the Role of Exercise in Inhibiting mTOR Signaling in Triple-Negative Breast Cancer

“…Aberrant activation of the PI3K/Akt/mTOR pathway is often found in human cancers and promotes cell proliferation [ 29 ]. Activation has been shown in the lung, head, and neck and breast, gynaecologic, colorectal, and prostate cancers and glioblastoma multiforme [ 30 ] and also in B-lineage acute lymphoblastic leukemia [ 31 ]. PI3Ks are pivotal molecules in this pathway and possess eight isoforms grouped into class I, class II, and class III.…”

Novel cancer therapies and their association with diabetes

“…PI3-K-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that regulates cellular proliferation, dehiscence and growth (Simioni et al 2018). Mutations affecting the PI 3-Kinase pathway are present in many human cancer cells making it a target for therapeutics designed to inhibit cancer progression.…”

“…Phosphoinositide-dependent serine threonine protein kinase (protein kinase B, Akt) is a key intermediary protein in the insulin signaling pathway especially in skeletal muscle and adipose tissue. Signaling through PI3-K/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) is also one of the fundamental pathways regulating cellular proliferation and growth (Simioni et al 2018). Thus, it has been a very active area in cancer therapy development since PI3K/Akt pathway mutations are essential for cancer cell proliferation and progression (Crouthamel et al 2009).…”