Abstract
Inhibition of PI3K in T-ALL selects for drug-resistant clones that have lost oncogenic NOTCH1.
Major finding: Inhibition of PI3K in T-ALL selects for drug-resistant clones that have lost oncogenic NOTCH1.
Mechanism: Downregulation of NOTCH1 restores PI3K–AKT signaling in PI3K inhibitor–resistant clones.
Impact: Dual therapy targeting NOTCH1 and PI3K may alter clonal selection and promote drug resistance.
Treatment of advanced cancers relies on drugs targeting specific pathways that are aberrantly regulated in tumor cells. In T-cell acute lymphoblastic leukemia (T-ALL), two pathways that are commonly deregulated are the RAS–PI3K and NOTCH1 pathways, supporting dual inhibition of these oncogenic pathways as a potential therapeutic strategy. Activation of PI3K in T-ALL is associated with drug resistance and poor prognosis, and a potent PI3K inhibitor, GDC-0941, is currently in clinical development. Using a retroviral insertional mutagenesis model of murine leukemia, Dail and colleagues found that GDC-0941 transiently extended the survival of leukemia-bearing mice. Combined treatment with a MEK inhibitor enhanced the efficacy of GDC-0941 in both Kras–wild-type and KrasG12D T-ALL; however, PI3K inhibitor–resistant leukemias eventually developed in all mice. Intriguingly, 61% of resistant tumors exhibited reduced expression of the active NOTCH1 protein and NOTCH1 transcriptional targets, decreased sensitivity to suppression of NOTCH1 with γ-secretase inhibitor, and loss of somatic NOTCH1 mutations that were present in the corresponding parental leukemias, suggesting that blocking PI3K imposed a selective pressure to downregulate NOTCH1 signaling. Resistant T-ALL cells demonstrated activation of the PI3K–AKT pathway compared to parental T-ALL cells and required higher concentrations of GDC-0941 to inhibit PI3K signaling. This increase in PI3K activity was mediated in part by loss of NOTCH1; enforced expression of active NOTCH1 increased T-ALL cell sensitivity to GDC-0941, whereas NOTCH1 inhibition enhanced PI3K activation and conferred resistance to GDC-0941, indicating that activated NOTCH1 suppresses PI3K signaling. These results confirm that T-ALL cells initially respond to targeted inhibition of the PI3K pathway and identify downregulation of NOTCH1 as a mechanism of acquired resistance. Additionally, these findings suggest that simultaneous use of inhibitors against both pathways may promote T-ALL drug resistance.
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