Novel pharmacological and dietary approaches to target mTOR in B-cell acute lymphoblastic leukemia

Abstract

High-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) are frequently associated with aberrant activation of tyrosine kinases (TKs). These include Ph+ B-ALL driven by BCR-ABL, and Ph-like B-ALL that carries other chromosomal rearrangements and/or gene mutations that activate TK signaling. Currently, the tyrosine kinase inhibitor (TKI) dasatinib is added to chemotherapy as standard of care in Ph+ B-ALL, and TKIs are being tested in clinical trials for Ph-like B-ALL. However, growth factors and nutrients in the leukemia microenvironment can support cell cycle and survival even in cells treated with TKIs targeting the driving oncogene. These stimuli converge on the kinase mTOR, whose elevated activity is associated with poor prognosis. In preclinical models of Ph+ and Ph-like B-ALL, mTOR inhibitors strongly enhance the anti-leukemic efficacy of TKIs. Despite this strong conceptual basis for targeting mTOR in B-ALL, the first two generations of mTOR inhibitors tested clinically (rapalogs and mTOR kinase inhibitors) have not demonstrated a clear therapeutic window. The aim of this review is to introduce new therapeutic strategies to the management of Ph-like B-ALL. We discuss novel approaches to targeting mTOR in B-ALL with potential to overcome the limitations of previous mTOR inhibitor classes. One approach is to apply third-generation bi-steric inhibitors that are selective for mTOR complex-1 (mTORC1) and show preclinical efficacy with intermittent dosing. A distinct, non-pharmacological approach is to use nutrient restriction to target signaling and metabolic dependencies in malignant B-ALL cells. These two new approaches could potentiate TKI efficacy in Ph-like leukemia and improve survival.

Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

“…This is expected since the substrates of ASCT2 and SNAT5 play pleiotropic roles in cell metabolism and are involved not only in protein synthesis but also in several other cell pathways, such as mTOR signalling 36,37 . Recently, novel pharmacological and dietary approaches have been proposed to inhibit mTOR activity, which is known to correlate with a poor prognosis in BCP‐ALL positive for the Philadelphia chromosome 38 . In a preliminary experiment, shown in Supplementary Material (Figure S8), both inhibitors GluγHA and V‐9302 have a marked inhibitory effect on the BCR‐ABL‐positive SUP‐B15 cell line.…”

PI3K/Akt/mTOR Signaling Pathway in Blood Malignancies—New Therapeutic Possibilities

“…The third generation of mTOR inhibitors is called RapaLinks or bi-steric mTORC1 inhibitors; these are made by connecting rapamycin and TOR-Ki. This generation embraces the action of both first-and second-generation mTOR inhibitors [84,85].…”

“…In in vitro research, RMC-4627 demonstrated strong and selective inhibition of 4E-BP1 phosphorylation specifically within B-ALL cell lines, while mTORC2 activity was unaffected. RMC-4627 reduced proliferation, decreased survival, and significantly increased the efficacy and tolerability of Dasatinib in a Ph+ B-ALL xenograft model [85,96]. It is worth adding that the first clinical candidate in the class of bi-steric mTORC1 inhibitor (RMC-5552) is undergoing clinical trials in solid tumors (NCT04774952) [97].…”