Targeting USP10–FAK pathway sensitizes BCR-ABL+ leukemia cells to tyrosine kinase inhibitors

BCR-ABL+ leukemia is driven by constitutive tyrosine kinase activity, and tyrosine kinase inhibitors (TKIs) are the standard therapy. However, resistance to TKIs remains a significant clinical challenge. In this study, we identify USP10 as a critical regulator in BCR-ABL+ leukemia cells and demonstrate its role in promoting resistance to TKIs. We show that USP10 is abnormally expressed in BCR-ABL+ leukemia cells. Inhibition of USP10, either via genetic knockdown or pharmacological inhibition, sensitizes BCR-ABL+ leukemia cells to TKIs, leading to increased cell death and suppressed cell growth. Furthermore, USP10 inhibitors synergize with TKIs to suppress TKI-resistant leukemia cells and primary cells from BCR-ABL+ leukemia patients. Mechanistically, USP10 promotes FAK phosphorylation, thereby activating pro-survival signaling pathways. In vivo, combination therapy with a USP10 inhibitor and a TKI significantly prolongs survival in a BCR-ABL+ leukemia mouse model. These findings establish USP10 as a key mediator of TKI resistance and underscore its potential as a therapeutic target to overcome drug resistance in BCR-ABL+ leukemia. ● BCR-ABL activity regulates USP10 expression. ● Inhibition of USP10 enhances TKI-induced apoptosis and suppresses leukemia cell growth, overcoming TKI resistance. ● USP10 inhibitors synergize with TKIs to improve therapeutic efficacy. ● USP10 promotes TKI resistance through FAK phosphorylation.