Inge Govaerts1,2,3, Cristina Prieto1,2,3, Charlien Vandersmissen1,2,3, Olga Gielen1,2,3, Kris Jacobs1,2,3, Sarah Provost1,2,3, David Nittner2, Johan Maertens3,4,5, Nancy Boeckx6,7, Kim De Keersmaecker3,7, Heidi Segers3,7,8, Jan Cools9,10,11. 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.
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.
Authors: Han-Zhou Qi; Jun Xu; Qian-Qian Yang; Ren Lin; Zhi-Xiang Wang; Ke Zhao; Qiang Wang; Xuan Zhou; Zhi-Ping Fan; Fen Huang; Na Xu; Li Xuan; Hua Jin; Jing Sun; Robert Peter Gale; Hong-Sheng Zhou; Qi-Fa Liu Journal: Bone Marrow Transplant Date: 2022-08-30 Impact factor: 5.174