title: Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment.
abstract: Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are two key components of the PI3K/Akt/mTOR signaling pathway. This signal transduction cascade regulates a wide range of physiological cell processes, that include differentiation, proliferation, apoptosis, autophagy, metabolism, motility, and exocytosis. However, constitutively active PI3K/Akt/mTOR signaling characterizes many types of tumors where it negatively influences response to therapeutic treatments. Hence, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors may improve cancer patient outcome. The PI3K/Akt/mTOR signaling cascade is overactive in acute leukemias, where it correlates with enhanced drug-resistance and poor prognosis. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds targeting the catalytic site of both kinases. In preclinical models, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against acute leukemia cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin. At variance with rapamycin, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited the rapamycin-resistant phosphorylation of eukaryotic initiation factor 4E-binding protein 1, resulting in a marked inhibition of oncogenic protein translation. Therefore, they strongly reduced cell proliferation and induced an important apoptotic response. Here, we reviewed the evidence documenting that dual PI3K/mTOR inhibitors may represent a promising option for future targeted therapies of acute leukemia patients.
authors.affiliation: Department of Human Anatomy, University of Bologna, Cellular Signalling Laboratory, Bologna, Italy. alberto.martelli@unibo.it
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cappellini
authors.forename: Francesca
authors.initials: F
authors.lastname: Buontempo
authors.forename: Daniela
authors.initials: D
authors.lastname: Bressanin
authors.forename: Milena
authors.initials: M
authors.lastname: Fini
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D000208:Acute Disease; D000818:Animals; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D058990:Molecular Targeted Therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054852:Small Molecule Libraries; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases