Targeting γ-secretase subunit PSEN1 blocks mutant NOTCH signaling in T-ALL without severe NOTCH toxicity.

  • Major finding: Targeting γ-secretase subunit PSEN1 blocks mutant NOTCH signaling in T-ALL without severe NOTCH toxicity.

  • Concept: PSEN1 inactivation reduces leukemic burden without affecting normal T-cell development.

  • Impact: Selective PSEN1 inhibitors are a potential therapy for patients with NOTCH-driven cancers.

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Gain-of-function NOTCH1 mutations are present in the majority of T-cell acute lymphoblastic leukemia (T-ALL) cases. NOTCH is processed and activated by γ-secretases, intramembrane-cleaving proteases composed of four different subunits. Use of nonspecific γ-secretase inhibitors to modulate oncogenic NOTCH signaling has failed in clinical trials for both solid and hematologic cancers due to severe on-target toxicity. Habets, de Bock, and colleagues sought to determine if targeting the most common γ-secretase subunit found in tumors could attenuate T-ALL while preserving NOTCH signaling in healthy tissues. Expression profiling of γ-secretase subunits in T-ALL samples and cell lines revealed normal expression of the presenilin-1 (PSEN1) subunit, but almost no PSEN2 expression. Knockout of Psen1 did not significantly affect normal T-cell development in vivo, suggesting that the second PSEN subunit of the γ-secretase complex, PSEN2, was sufficient to maintain normal DLL4-mediated NOTCH signaling. Inactivation of Psen1, however, reduced signaling of the mutant NOTCH1 common in T-ALL, leading to cell-cycle arrest. Psen1 deletion also increased survival in established in vivo models, thus providing evidence for the role of PSEN1 in the development of leukemia. In human patient-derived xenograft models of NOTCH-dependent leukemias, treatment with a selective PSEN1 inhibitor, MRK-560, reduced tumor growth, splenomegaly, and splenic leukemic cell infiltration. Additionally, MRK-560 significantly prolonged survival, even in mice with high leukemia burden. In contrast to global γ-secretase inhibitors, MRK-560 treatment did not result in pathologic changes associated with on-target NOTCH toxicity, such as changes in gastrointestinal structure, increased secretory goblet cells, or T-cell development defects. Together, these data demonstrate that inhibition of PSEN1 significantly attenuated development of T-ALL without affecting normal T-cell development or dose-limiting “on-target” toxicity and suggest that selective targeting of PSEN1 may provide a safe and efficacious therapeutic option for patients with T-ALL and other cancers with NOTCH1 mutations.

Habets RA, de Bock CE, Serneels L, Lodewijckx I, Verbeke D, Nittner D, et al. Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition. Sci Transl Med 2019;11:eaau6246.

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