Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Kinase inhibitor resistance is a major challenge in chronic myeloid leukemia (CML) treatment.
• While kinase domain mutations are known resistance mechanisms, non-mutational resistance pathways remain poorly understood.

Purpose of the Study:

• To investigate mechanisms of resistance to kinase inhibitors in CML in the absence of kinase domain mutations.
• To identify novel therapeutic strategies to overcome treatment resistance in CML.

Main Methods:

• In vitro assays using bone marrow microenvironment proteins to assess resistance mechanisms.
• Analysis of the FGF receptor 3/RAS/c-RAF/mitogen-activated protein kinase pathway activation.
• Clinical evaluation of CML patients resistant to ABL kinase inhibitors treated with ponatinib.
• Immunohistochemical analysis of bone marrow FGF2 levels in CML patients.

Main Results:

• Fibroblast growth factor 2 (FGF2) was identified as a key mediator promoting imatinib resistance in CML cells.
• FGF2 activates the FGF receptor 3/RAS/c-RAF/mitogen-activated protein kinase pathway, driving cell growth.
• Ponatinib, a multikinase inhibitor, effectively overcame FGF2-mediated resistance by targeting both BCR-ABL and FGF receptor.
• CML patients with non-mutational resistance exhibited higher bone marrow FGF2 levels and responded to ponatinib, with decreased FGF2 upon treatment.

Conclusions:

• Ligand-induced resistance, mediated by FGF2, is a clinically relevant mechanism in CML.
• Inhibition of FGF receptor represents a viable strategy to circumvent non-mutational resistance to ABL kinase inhibitors.
• Combination therapies targeting both BCR-ABL and FGF receptor signaling hold promise for overcoming resistance in CML.