Triterpenoid Exposure and HO-1 Blockade Sensitize Neoplastic Mast Cells Against Midostaurin and Avapritinib.

Authors

Max Vincent John, Yüksel Filik Schüppler, Nadine Witzeneder, Mathias Schneeweiss-Gleixner, Barbara Peter, Daniela Berger, Gabriele Stefanzl, Isma Ishaq-Parveen, Jun Fang, Waliul Islam, Juliana Schwaab, Andreas Reiter, Marina Konopleva, Michael Andreeff, Gregor Hoermann, Michel Arock, Johannes Zuber, Klaus Schmetterer, Wolfgang R Sperr, Peter Valent, Karoline V Gleixner

Published in

Cells. Volume 15. Issue 20. Oct 19, 2026. Epub Oct 19, 2026.

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.

PMID:
42929870
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.