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

Area of Science:

• Oncology
• Molecular Biology
• Systems Biology

Background:

• Therapeutic resistance in ~40% of relapsed/non-responder tumors lacks clear genetic cause, implicating intracellular communication.
• Understanding signaling pathway rewiring in resistant cells is vital for developing new cancer treatment strategies.

Purpose of the Study:

• To develop a novel strategy integrating phosphoproteomics and network analysis to understand signaling rewiring in therapy-resistant cancer cells.
• To elucidate BCR::ABL1-independent mechanisms driving relapse in chronic myeloid leukemia (CML) after therapy discontinuation.

Main Methods:

• Developed a multi-step strategy combining high-sensitivity mass spectrometry-based phosphoproteomics with network analysis.
• Constructed context-specific signaling networks to model pathway rewiring in drug-treated resistant and sensitive cells.
• Applied the strategy to patient-derived leukemic stem cells from CML patients.

Main Results:

• Elucidated BCR::ABL1-independent mechanisms driving CML relapse.
• Generated a signaling map detailing molecular mechanisms controlling proliferation, DNA damage response, and inflammation in resistant cells.
• Uncovered acquired FLT3-dependency as a key mechanism in therapy-resistant CML, validated in patient-derived cells.

Conclusions:

• Presented a novel, broadly applicable strategy for analyzing signaling rewiring in cancer.
• Identified FLT3 as a potential therapeutic target for relapsed CML patients, offering a new strategy for overcoming treatment resistance.