Triterpenoid Exposure and HO-1 Blockade Sensitize Neoplastic Mast Cells Against Midostaurin and Avapritinib
13 affiliations
- 1Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria
- 2Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria
- 3Department of Medicine III, Division of Hepatology and Gastroenterology, Medical University of Vienna, 1090 Vienna, Austria
- 4Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan
- 5Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- 6Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, 68167 Mannheim, Germany
- 7Departments of Oncology and Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- 8Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
- 9MLL Munich Leukemia Laboratory, 81377 Munich, Germany
- 10French Reference Network for Mastocytosis (CEREMAST) and Department of Hematological Biology, Pitié-Salpêtrière Hospital, AP-HP, Paris Sorbonne University, 75013 Paris, France
- 11Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), 1030 Vienna, Austria
- 12Medical University of Vienna, Vienna BioCenter (VBC), 1030 Vienna, Austria
- 13Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
Abstract
Advanced systemic mastocytosis (advSM), including aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL), are rare, mostly KIT D816V-driven malignancies with a poor prognosis. KIT D816V-targeting drugs, such as midostaurin or avapritinib, can induce hematologic responses in most patients with advSM. However, relapses may occur. Therefore, current research focuses on novel drugs and drug combinations to improve outcomes in advSM. We here describe that the synthetic triterpenoids bardoxolone methyl and omaveloxolone suppress proliferation in various human MCL-like cell lines expressing or lacking KIT D816V, with IC50 values of 0.2–0.4 µM. Growth-inhibitory effects were accompanied by induction of apoptosis, decreased surface expression of CD44, CD71 and KIT, and downregulation of cytoplasmic AKT. Antiproliferative effects of bardoxolone methyl and omaveloxolone were also observed in primary neoplastic cells obtained from patients with advSM. Moreover, both synthetic triterpenoids were found to cooperate with midostaurin and avapritinib in suppressing the proliferation of HMC-1 and MCPV-1 cells. However, bardoxolone methyl and omaveloxolone also augmented expression of heme oxygenase-1 (HO-1), a mediator of cell survival and drug resistance in these cells. The HO-1 inhibitor SMA-ZnPP was subsequently applied and found to sensitize neoplastic mast cells against synthetic triterpenoids and KIT D816V-targeting drugs. Together, application of bardoxolone methyl and omaveloxolone, as single agents or in drug combinations involving HO-1 blockers and/or KIT D816V-targeting drugs, may be a suitable strategy to improve therapy and to overcome resistance in advSM. The clinical value of this combination approach remains to be assessed in clinical trials.
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BibTeX
@article{john2026triterpenoid,
title = {{Triterpenoid Exposure and HO-1 Blockade Sensitize Neoplastic Mast Cells Against Midostaurin and Avapritinib}},
author = {Max Vincent John and Yüksel Filik Schüppler and Nadine Witzeneder and Mathias Schneeweiss-Gleixner and Barbara Peter and Daniela Berger and Gabriele Stefanzl and Isma Ishaq-Parveen and Jun Fang and Waliul Islam and Juliana Schwaab and Andreas Reiter and Marina Konopleva and Michael Andreeff and Gregor Hoermann and Michel Arock and Johannes Zuber and Klaus Schmetterer and Wolfgang R. Sperr and Peter Valent and Karoline V. Gleixner},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201898},
url = {https://www.mdpi.com/2073-4409/15/20/1898},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Triterpenoid Exposure and HO-1 Blockade Sensitize Neoplastic Mast Cells Against Midostaurin and Avapritinib
AU - Max Vincent John
AU - Yüksel Filik Schüppler
AU - Nadine Witzeneder
AU - Mathias Schneeweiss-Gleixner
AU - Barbara Peter
AU - Daniela Berger
AU - Gabriele Stefanzl
AU - Isma Ishaq-Parveen
AU - Jun Fang
AU - Waliul Islam
AU - Juliana Schwaab
AU - Andreas Reiter
AU - Marina Konopleva
AU - Michael Andreeff
AU - Gregor Hoermann
AU - Michel Arock
AU - Johannes Zuber
AU - Klaus Schmetterer
AU - Wolfgang R. Sperr
AU - Peter Valent
AU - Karoline V. Gleixner
PY - 2026
DA - 2026/10/19
JO - Cells
DO - 10.3390/cells15201898
UR - https://www.mdpi.com/2073-4409/15/20/1898
AB - Advanced systemic mastocytosis (advSM), including aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL), are rare, mostly KIT D816V-driven malignancies with a poor prognosis. KIT D816V-targeting drugs, such as midostaurin or avapritinib, can induce hematologic responses in most patients with advSM. However, relapses may occur. Therefore, current research focuses on novel drugs and drug combinations to improve outcomes in advSM. We here describe that the synthetic triterpenoids bardoxolone methyl and omaveloxolone suppress proliferation in various human MCL-like cell lines expressing or lacking KIT D816V, with IC50 values of 0.2–0.4 µM. Growth-inhibitory effects were accompanied by induction of apoptosis, decreased surface expression of CD44, CD71 and KIT, and downregulation of cytoplasmic AKT. Antiproliferative effects of bardoxolone methyl and omaveloxolone were also observed in primary neoplastic cells obtained from patients with advSM. Moreover, both synthetic triterpenoids were found to cooperate with midostaurin and avapritinib in suppressing the proliferation of HMC-1 and MCPV-1 cells. However, bardoxolone methyl and omaveloxolone also augmented expression of heme oxygenase-1 (HO-1), a mediator of cell survival and drug resistance in these cells. The HO-1 inhibitor SMA-ZnPP was subsequently applied and found to sensitize neoplastic mast cells against synthetic triterpenoids and KIT D816V-targeting drugs. Together, application of bardoxolone methyl and omaveloxolone, as single agents or in drug combinations involving HO-1 blockers and/or KIT D816V-targeting drugs, may be a suitable strategy to improve therapy and to overcome resistance in advSM. The clinical value of this combination approach remains to be assessed in clinical trials.
SN - 2073-4409
ER -