A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia

A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia

Abstract Background About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose...

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Main Authors: Valeria Bica, Veronica Venafra, Giorgia Massacci, Simone Graziosi, Sara Gualdi, Gessica Minnella, Federica Sorà, Patrizia Chiusolo, Maria Elsa Brunetti, Gennaro Napolitano, Massimo Breccia, Dimitrios Mougiakakos, Martin Böttcher, Thomas Fischer, Livia Perfetto, Francesca Sacco
Format: Article
Language:English
Published: BMC 2025-04-01
Series:Cell Communication and Signaling
Subjects:
Chronic myeloid leukemia
BCR:ABL1-independent resistance
Signaling pathways
Phosphoproteomics
Computational strategy
Drug repurposing
Online Access:https://doi.org/10.1186/s12964-025-02185-0
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Summary:Abstract Background About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose alternative effective strategies for cancer patients. Methods To achieve this goal, we developed a novel multi-step strategy, which integrates high sensitive mass spectrometry-based phosphoproteomics with network-based analysis. This strategy builds context-specific networks recapitulating the signaling rewiring upon drug treatment in therapy-resistant and sensitive cells. Results We applied this strategy to elucidate the BCR::ABL1-independent mechanisms that drive relapse upon therapy discontinuation in chronic myeloid leukemia (CML) patients. We built a signaling map, detailing - from receptor to key phenotypes - the molecular mechanisms implicated in the control of proliferation, DNA damage response and inflammation of therapy-resistant cells. In-depth analysis of this map uncovered novel therapeutic vulnerabilities. Functional validation in patient-derived leukemic stem cells revealed a crucial role of acquired FLT3-dependency and its underlying molecular mechanism. Conclusions In conclusion, our study presents a novel generally applicable strategy and the reposition of FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for CML relapsed patients.
ISSN:1478-811X

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