Reference Detail

Ref Type

Journal Article

PMID

(39395205)

Authors

Seale TS, Li L, Bruner JK, Chou M, Nguyen B, Seo J, Zhu R, Levis MJ, Pratilas CA, Small D

Title

Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular oncology			2024 Oct 12		Mol Oncol

URL

Abstract Text

Acute myeloid leukemia (AML) patients with the FMS-related receptor tyrosine kinase 3 internal tandem duplication (FLT3/ITD) mutation have a poorer prognosis, and treatment with FLT3 tyrosine kinase inhibitors (TKIs) has been hindered by resistance mechanisms. One such mechanism is known as adaptive resistance, in which downstream signaling pathways are reactivated after initial inhibition. Past work has shown that FLT3/ITD cells undergo adaptive resistance through the reactivation of extracellular signal-regulated kinase (ERK) signaling within 24 h of sustained FLT3 inhibition. We investigated the mechanism(s) responsible for this ERK reactivation and hypothesized that targeting tyrosine-protein kinase receptor UFO (AXL), another receptor tyrosine kinase that has been implicated in cancer resistance, may overcome the adaptive ERK reactivation. Experiments revealed that AXL is upregulated and activated in FLT3/ITD cell lines mere hours after commencing TKI treatment. AXL inhibition combined with FLT3 inhibition to decrease the ERK signal rebound and to exert greater anti-leukemia effects than with either treatment alone. Finally, we observed that TKI-induced AXL upregulation occurs in patient samples, and combined inhibition of both AXL and FLT3 increased efficacy in our in vivo models. Taken together, these data suggest that AXL plays a role in adaptive resistance in FLT3/ITD AML and that combined AXL and FLT3 inhibition might improve FLT3/ITD AML patient outcomes.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Bemcentinib + Gilteritinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Bemcentinib (BGB-324) and Xospata (gilteritinib) synergistically inhibited proliferation and induced apoptosis in an acute myeloid leukemia cell line harboring a FLT3-ITD (PMID: 39395205).	39395205
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Dubermatinib + Gilteritinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with the combination of Dubermatinib (TP-0903) and Xospata (gilteritinib) inhibited proliferation and synergistically induced apoptosis in an acute myeloid leukemia cell line and in patient-derived cells harboring a FLT3-ITD in culture, and led to a greater decrease in leukemic burden and improved survival compared to treatment with either agent alone in a cell line xenograft model (PMID: 39395205).	39395205
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Dubermatinib + Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Dubermatinib (TP-0903) and Nexavar (sorafenib) inhibited proliferation of an acute myeloid leukemia cell line harboring a FLT3-ITD in culture (PMID: 39395205).	39395205
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Bemcentinib + Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Bemcentinib (BGB-324) and Nexavar (sorafenib) synergistically inhibited proliferation of an acute myeloid leukemia cell line harboring a FLT3-ITD (PMID: 39395205).	39395205