p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, chemotherapy-resistant sarcomas, particularly in neurofibromatosis type 1 (NF1).
• TP53 mutations correlate with poor survival in MPNSTs, but the underlying mechanisms in NF1 deficiency remain unclear.
• MET amplification is an early event in MPNST progression, and its inhibition is a therapeutic target.

Purpose of the Study:

• To investigate the roles of MET and TP53 in kinome reprogramming and cellular differentiation in preclinical MPNST models.
• To elucidate the mechanisms of therapy resistance mediated by p53 in the context of NF1-deficient MPNSTs.

Main Methods:

• Utilized preclinical MPNST mouse models.
• Evaluated the impact of Trp53 loss on MET stability, localization, and signaling pathways (RAS/ERK, AKT).
• Assessed sensitivity to MET, MEK, and mTOR inhibitors.
• Analyzed kinome reprogramming and activation of differentiation genes.

Main Results:

• p53 loss alters MET stability and signaling, leading to kinome reprogramming and lineage plasticity, contributing to therapy resistance.
• Trp53 loss shifted signaling from RAS/ERK to AKT pathways.
• Trp53-deficient MPNSTs showed enhanced sensitivity to MEK and mTOR inhibition.
• Therapeutic inhibition resulted in heterogeneous activation of differentiation genes in Trp53-deficient cells.

Conclusions:

• p53 loss drives MPNST therapy resistance by altering MET dependency, promoting kinome reprogramming, and enabling phenotypic flexibility.
• Understanding these mechanisms is crucial for developing effective therapeutic strategies for NF1-associated MPNSTs.
• Targeting downstream pathways like AKT, MEK, or mTOR may overcome resistance in p53-mutated MPNSTs.