Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update.
Camilla EvangelistiFrancesca ChiariniJames A McCubreyAlberto Maria MartelliPublished in: International journal of molecular sciences (2018)
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.
Keyphrases
- cell proliferation
- acute lymphoblastic leukemia
- drug resistant
- end stage renal disease
- newly diagnosed
- ejection fraction
- multidrug resistant
- prognostic factors
- chronic kidney disease
- healthcare
- endothelial cells
- acute myeloid leukemia
- young adults
- small cell lung cancer
- cell cycle
- squamous cell carcinoma
- signaling pathway
- stem cells
- diffuse large b cell lymphoma
- peritoneal dialysis
- bone marrow
- small molecule
- risk assessment
- mesenchymal stem cells
- cancer therapy
- squamous cell
- acinetobacter baumannii
- binding protein
- patient reported outcomes
- cystic fibrosis
- smoking cessation
- human health
- pluripotent stem cells
- replacement therapy