Glutaminase Inhibition Synergizes with NOTCH1 Inhibition in T-ALL

Aberrant NOTCH1 signaling is implicated in the majority of cases of T-cell acute lymphoblastic leukemia (T-ALL), but inhibition of NOTCH1 using small-molecule γ-secretase inhibitors (GSI) has met with limited clinical success. GSI resistance has been attributed to mutational loss of the PTEN tumor suppressor, leading Herranz and colleagues to explore the specific mechanisms by which PTEN inactivation drives GSI resistance. In a mouse model of NOTCH1-induced T-ALL, Pten loss and consequent constitutive activation of PI3K–AKT signaling, which is known to induce glycolysis, abrogated the antitumor effect of GSI therapy. Gene expression profiling revealed that anti-NOTCH1 therapy suppressed anabolism and increased catabolism, apoptosis, and autophagy in Pten-positive, but not Pten-deleted, leukemias, indicating that NOTCH1 inhibition creates a metabolic crisis in Pten-positive T-ALL cells that confers reliance on the autophagy salvage pathway. Consistent with this finding, suppression of autophagy enhanced the antileukemic effect of NOTCH1 inhibition. Metabolic tracing studies revealed that NOTCH1-induced leukemia cells used glutamine as a primary source of carbon, that NOTCH1 inhibition impaired both glutaminolysis and glycolysis, and that Pten deletion attenuated the decrease in glycolytic efficiency mediated by NOTCH1 blockade, suggesting that Pten loss induces glycolysis to overcome NOTCH1 inhibition. In mice with Pten-positive NOTCH1-induced leukemia, GSI therapy eventually led to drug resistance and disease progression, which was accompanied by lower Pten expression and higher expression of glutaminase. Overexpression of glutaminase was sufficient to confer resistance to NOTCH1 inhibition, whereas combined treatment with GSI and the glutaminase inhibitor BPTES showed strong and synergistic antitumor effects in Pten-positive, but not Pten-deleted, T-ALL cell lines, human leukemia xenografts, and mouse models. These results indicate that glutaminolysis provides a primary energy source for Pten-positive leukemia cell survival downstream of NOTCH1 signaling and suggest that glutaminase inhibition may be a viable therapeutic strategy to improve the efficacy of GSIs in the treatment of T-ALL.

Herranz D, Ambesi-Impiombato A, Sudderth J, Sánchez-Martín M, Belver L, Tosello V, et al. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat Med 2015;21:1182–9.

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