Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia

The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBP alpha activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBP alpha activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBP alpha inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBP alpha activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBP alpha activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy. Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBP alpha activation as a mechanism of FLT3i resistance and therapeutically target C/EBP alpha activation in combination with FLT3i in preclinical models FLT3-ITD AML.

Automated summary

By analyzing data from primary AML patient samples, C/EBP alpha activation is identified as a major mechanism of resistance to FLT3 inhibitors (FLT3i). Inactivation of C/EBP alpha enhances the efficacy of FLT3i, and the antihypertensive medication guanfacine mimics the inactivation of C/EBP alpha, showing a synergistic effect with FLT3i. These findings highlight the targetability of C/EBP alpha activation as a mechanism of resistance and support clinical studies to test the combination of guanfacine with FLT3i.