XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia
Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang
Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang
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Research Article Cell biology Clinical Research Hematology

XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia

Abstract

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive aggressive acute myeloid leukemia (AML) and confer poor prognosis. Although FLT3 inhibitors have improved AML outcomes, their efficacy is frequently limited by microenvironment-mediated signaling and treatment-emergent resistance. XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for multiple solid tumors. Biochemical, multi-omics, and functional analyses showed that XY0206 directly engages FLT3 and suppresses downstream STAT5, AKT, and ERK signaling, resulting in apoptosis of AML cells with FLT3–internal tandem duplications (FLT3-ITD). Across models of FLT3-dependent resistance, XY0206 retained antileukemic activity, including in FLT3-ITD cells harboring the F691L gatekeeper mutation, a recurrent alteration conferring resistance to approved FLT3 inhibitors. In primary AML blasts and xenograft models, XY0206 exhibited enhanced antileukemic activity with favorable tolerability relative to gilteritinib. In a phase I/II trial of XY0206 monotherapy in patients with relapsed or refractory (R/R) AML (ClinicalTrials.gov identifier NCT04471064), XY0206 achieved a composite complete remission rate (CRc) of 45.7% overall, with a notable 60.0% CRc rate among patients with FLT3-ITD mutations. Three of 8 patients with prior FLT3 inhibitor–exposed R/R AML also achieved CRc. Together, these findings support further clinical evaluation of XY0206 as an FLT3-directed therapeutic in AML, particularly in disease settings with reduced sensitivity to existing FLT3 inhibitors.

Authors

Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang

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Figure 4

XY0206 retains activity in FLT3-ITD AML with growth factor—associated and acquired resistance.

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XY0206 retains activity in FLT3-ITD AML with growth factor—associated an...
(A) CCK-8 viability assays of MV4-11 and MOLM13 cells treated with XY0206, gilteritinib, or sunitinib for 3 days with or without FGF2 (10 ng/mL). (B) Growth kinetics of MV4-11 and MOLM13 cells cultured with or without FGF2 (20 ng/mL) and treated at respective IC50 concentrations. Cells were counted every 2 or 3 days for up to 10 days (MV4-11) or 8 days (MOLM13). (C) Immunoblot analysis of phosphorylated and total FLT3, STAT5, AKT, and ERK1/2 in MV4-11 and MOLM13 cells treated with XY0206, gilteritinib, or sunitinib for 10 minutes with or without FGF2. Conc, concentration. (D) Schematic of GilR cell generation and gilteritinib IC50 determination. (E) WES analysis of GilR cells showing acquired genetic alterations relative to MOLM13. VAF, variant allele frequency. (F) CCK-8 dose-response curves of parental MOLM13 and GilR cells treated with increasing concentrations of XY0206, gilteritinib, or sunitinib for 72 hours. (G) Proliferation of GilR cells treated with XY0206, gilteritinib, or sunitinib (80 nM), measured every 2 days for 8 days. (H) Cell cycle distribution of GilR cells treated with XY0206 (XY), gilteritinib (Gil), or sunitinib (Suni) for 24 hours. (I) Apoptosis of GilR cells treated with XY0206, gilteritinib, or sunitinib for 72 hours. (J) Immunoblot analysis of total and phosphorylated FLT3, STAT5, AKT, and ERK1/2 in GilR cells treated for 4 hours. Numbers below blots in C and J indicate densitometric ratios normalized to vehicle controls. Data are mean ± SD from 3 independent biological experiments for A, B, and F–I. Statistical analyses were performed using 2-way ANOVA with Tukey’s test for B and G and 1-way ANOVA with Tukey’s test for H and I. *P < 0.05, ***P < 0.001. Immunoblots in C and J were repeated independently at least twice with similar results.