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

Author(s)

de Macedo, Brunno Gilberto Santos ; de Melo, Manuela Albuquerque ; Pereira-Martins, Diego Antonio ; Machado-Neto, Joao Agostinho ; Traina, Fabiola

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 14, n. 1, p. 10-pg., 2024-10-12.

Abstract

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies. (AU)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 21/11112-0 - Assessment of autophagy as a therapeutic efficiency limiting mechanism of FLT3 pharmacological inhibitors on acute myeloid leukemia
• Grantee: Manuela Albuquerque de Melo
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 22/03871-1 - Functional and molecular investigation of the correlation between autophagy, NLRP3-inflammasome and hemostasis on acute myeloid leukemia
• Grantee: Brunno Gilberto Santos de Macedo
• Support Opportunities: Scholarships in Brazil - Master