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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月10日

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  • 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

摘要

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.