1. Academic Validation
  2. PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia

PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia

  • J Hematol Oncol. 2021 Jun 24;14(1):97. doi: 10.1186/s13045-021-01114-1.
Inge Govaerts 1 2 3 Cristina Prieto 1 2 3 Charlien Vandersmissen 1 2 3 Olga Gielen 1 2 3 Kris Jacobs 1 2 3 Sarah Provost 1 2 3 David Nittner 2 Johan Maertens 3 4 5 Nancy Boeckx 6 7 Kim De Keersmaecker 3 7 Heidi Segers 3 7 8 Jan Cools 9 10 11
Affiliations

Affiliations

  • 1 Center for Human Genetics, KU Leuven, Leuven, Belgium.
  • 2 Center for Cancer Biology, VIB, Leuven, Belgium.
  • 3 Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium.
  • 4 Department of Hematology, UZ Leuven, Leuven, Belgium.
  • 5 Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
  • 6 Department of Laboratory Medicine, UZ Leuven, Leuven, Belgium.
  • 7 Department of Oncology, KU Leuven, Leuven, Belgium.
  • 8 Department of Pediatric Oncology, UZ Leuven, Leuven, Belgium.
  • 9 Center for Human Genetics, KU Leuven, Leuven, Belgium. jan.cools@kuleuven.be.
  • 10 Center for Cancer Biology, VIB, Leuven, Belgium. jan.cools@kuleuven.be.
  • 11 Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium. jan.cools@kuleuven.be.
Abstract

Background: T cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype that comprises 10-15% of childhood and 20-25% of adult ALL cases. Over 70% of T-ALL patients harbor activating mutations in the NOTCH1 signaling pathway and are predicted to be sensitive to gamma-secretase inhibitors. We have recently demonstrated that selective inhibition of PSEN1-containing gamma-secretase complexes can overcome the dose-limiting toxicity associated with broad gamma-secretase inhibitors. In this study, we developed combination treatment strategies with the PSEN1-selective gamma-secretase inhibitor MRK-560 and other targeted agents (kinase inhibitors ruxolitinib and imatinib; XPO-1 inhibitor KPT-8602/eltanexor) for the treatment of T-ALL.

Methods: We treated T-ALL cell lines in vitro and T-ALL patient-derived xenograft (PDX) models in vivo with MRK-560 alone or in combination with other targeted inhibitors (ruxolitinib, imatinib or KPT-8602/eltanexor). We determined effects on proliferation of the cell lines and leukemia development and survival in the PDX models.

Results: All NOTCH1-signaling-dependent T-ALL cell lines were sensitive to MRK-560 and its combination with ruxolitinib or imatinib in JAK1- or ABL1-dependent cell lines synergistically inhibited leukemia proliferation. We also observed strong synergy between MRK-560 and KPT-8602 (eltanexor) in all NOTCH1-dependent T-ALL cell lines. Such synergy was also observed in vivo in a variety of T-ALL PDX models with NOTCH1 or FBXW7 mutations. Combination treatment significantly reduced leukemic infiltration in vivo and resulted in a survival benefit when compared to single treatment groups. We did not observe weight loss or goblet cell hyperplasia in single drug or combination treated mice when compared to control.

Conclusions: These data demonstrate that the antileukemic effect of PSEN1-selective gamma-secretase inhibition can be synergistically enhanced by the addition of other targeted inhibitors. The combination of MRK-560 with KPT-8602 is a highly effective treatment combination, which circumvents the need for the identification of additional mutations and provides a clear survival benefit in vivo. These promising preclinical data warrant further development of combination treatment strategies for T-ALL based on PSEN1-selective gamma-secretase inhibition.

Keywords

Gamma-secretase complex; Leukemia; Mouse models; Nuclear export; Oncogenes; Signaling; Targeted therapy; Toxicity.

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