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

• Published in: Journal of cellular physiology 2018-10, Vol.233 (10), p.6440-6454
• Main Authors: Simioni, Carolina, Martelli, Alberto M., Zauli, Giorgio, Vitale, Marco, McCubrey, James A., Capitani, Silvano, Neri, Luca M.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute lymphoblastic leukemia; AKT protein; Anticancer properties; Antitumor activity; B‐ALL; Cancer; Cell proliferation; Clinical trials; combination therapy; Inhibitors; Kinases; Leukemia; Lymphatic leukemia; Medical prognosis; Medical research; Patients; Pediatrics; PI3K/Akt/mTOR signaling; Prognosis; protein kinase inhibitors; Radiation therapy; Rapamycin; Side effects; Signal transduction; Signaling; Survival; targeted therapy; TOR protein; Toxicity
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26539

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. The phosphatidylinositol 3‐phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory network which controls proliferation, survival, and drug‐resistance of cancer cells where it is frequently upregulated. Promising preclinical data on PI3K/Akt/mTOR inhibitors have demonstrated their anticancer activity in B‐lineage acute lymphoblastic leukemia (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 also the use of traditional chemotherapeutics or other novel, targeted agents.