Targeting mTOR in Acute Lymphoblastic Leukemia

Abstract

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure.

Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia

“…In addition to dual inhibitors, several selective mTOR kinase modulators have been developed in the last two decades [111]. These small molecules target the mTOR catalytic subunit of the mTORC1 and mTORC2 complexes [111].…”

“…In addition to dual inhibitors, several selective mTOR kinase modulators have been developed in the last two decades [111]. These small molecules target the mTOR catalytic subunit of the mTORC1 and mTORC2 complexes [111]. For example, PP242 (also known as Torkinib) is a potent, selective, and ATP-competitive inhibitor of mTOR, and it is among the most broadly used in preclinical models because of the demonstrated anti-proliferative and pro-apoptotic activity in several cancer models, including ALL [37].…”

miRNAs as Influencers of Cell–Cell Communication in Tumor Microenvironment

“…The PI3K/Akt/mTOR signalling pathway regulates several cellular processes, including cell proliferation and cell-cycle progression, survival, cell metabolism, and transcription [101]. PTEN is one of the main negative regulators of this pathway, mediating the dephosphorylation of Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3) to PIP2 and preventing the activation of the pathway [128]. In this view, PTEN acts as a tumor suppressor, preventing PI3K/Akt/mTOR activation, and is highly mutated in a variety of human cancers, including breast cancer, melanoma, and lung and prostate carcinoma [127,129].…”

mTOR Signaling in Metabolism and Cancer

“…Acute lymphoblastic leukemia (ALL) is one of the aggressive hematologic malignancies that occurs in both children and adults [ 6 ]. Simioni et al (2019) reviewed the advances in targeted therapy for ALL using mTOR inhibitors [ 7 ]. Constitutive activation of mTOR pathway is associated with deregulated production of malignant lymphoid cells and chemotherapeutic resistance in ALL.…”