Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia

Acute myeloid leukemia (AML) is not only clinically diverse and severe but also characterized by a complex molecular landscape that reshapes biological processes to promote disease initiation and persistence. Among the key molecular drivers are FLT3 mutations, which occur frequently and play a cooperative role in AML progression. Targeting these mutations through FLT3 inhibition has become a central therapeutic strategy. However, this approach faces significant obstacles, including intrinsic and acquired drug resistance. To address these challenges, we explored the interplay between autophagy and inflammasome activity, aiming to determine whether targeting this interaction could enhance FLT3 inhibition.

Our findings revealed a strong positive correlation between the expression of genes linked to autophagy and inflammasome activation. Gene set enrichment analysis of FLT3-ITD samples, along with their Compound 3 ex vivo responses to five FLT3 inhibitors, identified a shared molecular signature indicative of autophagy and inflammasome activation in poor responders. Notably, inflammasome activation was associated with an increased likelihood of resistance to the FLT3 inhibitors quizartinib and sorafenib. These results highlight a distinct molecular pattern in FLT3-ITD AML, emphasizing the need to further investigate how modulating these interconnected pathways could improve therapeutic outcomes.