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 5

XY0206 demonstrates antileukemic activity with favorable tolerability in patient-derived AML blasts and preclinical mouse models.

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XY0206 demonstrates antileukemic activity with favorable tolerability in...
(A) Cell viability of primary FLT3-ITD AML blasts (AML01 and AML02) treated with sorafenib, gilteritinib, or XY0206 for 72 hours; IC50 values were calculated using GraphPad Prism. (B) Viable cell counts of primary AML blasts after 48-hour treatment with sorafenib (Sora), gilteritinib (Gil), or XY0206 (XY). (C) Apoptosis of primary AML blasts after 48-hour treatment with sorafenib, gilteritinib, or XY0206, assessed by annexin V/PI staining and flow cytometry. (D) Immunoblot analysis of phosphorylated and total FLT3, STAT5, AKT, and ERK1/2 in AML01 cells treated with XY0206 for 24 hours. Numbers below blots indicate densitometric ratios normalized to total protein and scaled to vehicle control. (E) Viability of CBMC01 and CBMC02 treated with increasing concentrations of XY0206 for 72 hours. (F) Schematic of the cell line-derived xenograft model and treatment schedule. D, day. (G and H) Representative longitudinal bioluminescence images and quantification of leukemia burden in mice treated with vehicle, XY0206, gilteritinib, or sunitinib. Imaging was performed every 3 or 4 days. (I) Body-weight monitoring during treatment. (J) Kaplan-Meier survival analysis from an independent cohort treated with the same dosing schedule. n = 6 mice per group. Data are mean ± SD from 3 independent experiments for A–C and E, and from 5 mice/group for H and I. For B and C, multigroup comparisons were analyzed by 1-way ANOVA with Tukey’s test and 2-group comparisons by 2-tailed unpaired Student’s t test. For data reported in H and I, 2-way ANOVA with Tukey’s test was used. For data reported in J, a log-rank test was used. *P < 0.05, **P < 0.01, ***P < 0.001. Immunoblots in D were repeated independently at least twice with similar results.