Differential Effects of Selective Inhibitors Targeting the PI3K/AKT/mTOR Pathway in Acute Lymphoblastic Leukemia

Abstract

PurposeAberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established.Experimental DesignWe compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative.ResultsDual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2.ConclusionsInhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes.

Control of B lymphocyte development and functions by the mTOR signaling pathways

“…PI3Kα and PI3Kδ inhibitors alpelisib and idelalisib were also tested in this study, and the dual PI3K/mTOR inhibitor gedatolisib was the most effective treatment in 9/10 tumors. This finding confirmed earlier studies comparing dual PI3K/mTOR inhibitors with selective PI3K, mTORC1, and mTORC1/2 kinase inhibitors [146]. Examples of TOR-KIs being tested in clinical trials as single-agent treatments for B cell neoplasms (such as ALL and NHL) include MLN0128, CC-115, PQR-309 and CC-223.…”

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

“…37 Based on extensive preclinical data, other dual inhibitors are in clinical development. [38][39][40] …”

Recent insights into the pathophysiology of mTOR pathway dysregulation

“…Thus, RAD001 treatment alone is unlikely to be effective in ALL, and a dual inhibitor drug targeting approach is likely to be more effective in a broader range of ALL cells. 100 Dysregulated mTOR signaling in other human diseases: review of recent data Cardiovascular disorders mTOR plays a fundamental role in cardiomyocyte growth, development, and function. Cardiomyocyte specific deletion of mTOR is a lethal mutation affecting 92% of mice by the end of gestation.…”