Outlook on PI3K/AKT/mTOR inhibition in acute leukemia

Abstract

Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy.

Caspase-3 controls AML1-ETO–driven leukemogenesis via autophagy modulation in a ULK1-dependent manner

“…In AML, mTOR activation is seen in nearly all AML cases, as is phosphorylation of downstream targets such as p70S6, S6RP, and 4EBP1. [53][54][55] Clinical data suggest that mTOR inhibitors have potential therapeutic roles in a number of hematologic malignancies, including acute lymphoblastic leukemia, chronic myelogenous leukemia, mantle cell lymphoma, anaplastic large-cell lymphoma, and lymphoproliferative disorders. 56 All of these studies reveal that targeting mTORcentered autophagy may have broad therapeutic benefit.…”

mTORC signaling in hematopoiesis

“…The PI3K-AKT-mTOR pathway is hyperactive in patient-derived AML cells. However, rapamycin and its analogs failed to provide a significant improvement of response in leukemia patients [87], most likely due to the negative feedback loops. The elevation of RTK-PI3K-PDK1 activity in response to rapamycin can promote Akt phosphorylation on Thr308, which may be sufficient for cell survival [88].…”

“…Torin-2, an ATP-competitive inhibitor of mTOR, causes both apoptosis and autophagy and suppresses the cell cycle by affecting both mTORC1 and mTORC2 activities [93,95]. However, no clinical data for TOR-KIs have been reported thus far [87]. The compounds NVP-BEZ235 and XL-765 (Exelixis) simultaneously inhibit PI3K and mTOR kinases and decrease the phosphorylation of Akt, S6K1, and 4E-BP1.…”

Will targeting PI3K/Akt/mTOR signaling work in hematopoietic malignancies?

“…Fransecky et al reviewed the preclinical and clinical trials of these aforementioned inhibitors in AML, B-ALL, B-CLL, T-ALL, non-Hodgkin lymphoma (NHL), and MDS, but found that the clinical trial data are rather disappointing (73). In addition to the four main inhibitors that targeting the PI3K/Akt/mTOR signaling pathway, many other inhibitors are also in development.…”