Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia
Ji Eun Shin, Soo‐Hyun Kim, Mingyu Kong, Hwa-Ryeon Kim, Sungmin Yoon, Kyung‐Mi Kee, Jung Ah Kim, Dong Hyeon Kim, So Yeon Park, Jae Hyung Park, Hongtae Kim, Kyoung Tai No, Han‐Woong Lee, Heon Yung Gee, Seunghee Hong, Kun‐Liang Guan, Jae‐Seok Roe, Hyunbeom Lee, Dong‐Wook Kim, Hyun Woo Park
Abstract
Abstract Background Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. Methods We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3 + CML patients. Results We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3 + BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3 + BP-CML patients had significantly less favorable prognosis than FLT3 − patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3 + BCR::ABL1 cells and mouse xenograft models. Conclusion Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies. Graphical Abstract