bioRxiv

Kangboonruang K., Drabent P., Maksut F., Heintzé M., Lepelletier Y., Lhermitte L., Feroul M., Letard S., Kaboré C., Brenet F., Méni C., Cagnard N., Bondet V., Lefèvre G., Bruneau J., Dussiot M., Halse H., Bigorgne A., Collange A., Bouktit H., Rétornaz F., Megret J., Barete S., Droin N., Livideanu C., Lebouvier A., Duffy D., Solary E., Arock M., Gandhi D., Bodemer C., Rossignol J., Polivka L., Molina T., Hermine O., Maouche-Chrétien L.

Source :

openRxiv

2026 jan 16

Pmid / DOI:

10.1101/2025.11.03.686205

Abstract

Mastocytosis is a clonal disorder driven by
KIT
mutations, but resistance to tyrosine kinase inhibitors (TKIs) remains a major challenge. Following the discovery of an
AXL
L197M mutation in a patient with congenital aggressive mastocytosis, we demonstrated unexpected wild-type AXL expression in neoplastic mast cells (MCs) across mastocytosis subtypes, challenging current views concerning mastocytosis pathophysiology. AXL was undetectable in steady-state MCs but several factors, including IFN-α and IFN-β, induced its expression, consistent with the inflammatory nature of mastocytosis and the high interferon levels in patient plasma.

Ectopic expression of WT or L197M
AXL
in the ROSA
KIT
D816V cell line enhanced proliferation and survival by upregulating pSTAT5, pSTAT3, pFAK, p-p38α, survivin and BCL2. Both AXL forms conferred resistance to the KIT inhibitor PKC412/midostaurin by sustaining BCL2, MCL1, and BCL-XL expression while reducing caspase-3 activation. L197M
AXL
induced slightly stronger resistance to apoptosis than WT, but this difference was not significant. Combined KIT and AXL targeting (PKC412+R428) restored TKI sensitivity by downregulating BCL-XL, Livin and cIAP1, and activating caspase-3, highlighting the therapeutic potential of dual KIT/AXL pathway inhibition. Importantly, neoplastic MCs from a mast cell leukemia patient harboring the
KIT
F522C mutation and unresponsive to PKC412 strongly expressed AXL and displayed marked
in vitro
sensitivity to R428 alone, highlighting AXL as a potential therapeutic target in aggressive mastocytosis not driven by
KIT
D816V.

These findings identify AXL as a previously unrecognized driver of malignant MC survival and TKI resistance, and support AXL inhibition as a promising therapeutic strategy in aggressive mastocytosis.

–
AXL is aberrantly expressed in neoplastic mast cells, driving survival and resistance to KIT inhibition in mastocytosis.

–
Dual KIT and AXL inhibition restores TKI sensitivity in KIT-mutant mastocytosis.

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